Torsades de Pointes: A malignant form of polymorphic ventricular tachycardia that is characterized by HEART RATE between 200 and 250 beats per minute, and QRS complexes with changing amplitude and twisting of the points. The term also describes the syndrome of tachycardia with prolonged ventricular repolarization, long QT intervals exceeding 500 milliseconds or BRADYCARDIA. Torsades de pointes may be self-limited or may progress to VENTRICULAR FIBRILLATION.Phosphoric Diester Hydrolases: A class of enzymes that catalyze the hydrolysis of one of the two ester bonds in a phosphodiester compound. EC 3.1.4.Long QT Syndrome: A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.DNA Breaks, Single-Stranded: Interruptions in one of the strands of the sugar-phosphate backbone of double-stranded DNA.DNA Topoisomerases, Type I: DNA TOPOISOMERASES that catalyze ATP-independent breakage of one of the two strands of DNA, passage of the unbroken strand through the break, and rejoining of the broken strand. DNA Topoisomerases, Type I enzymes reduce the topological stress in the DNA structure by relaxing the superhelical turns and knotted rings in the DNA helix.Glycolates: Derivatives of ACETIC ACID which contain an hydroxy group attached to the methyl carbon.Phenethylamines: A group of compounds that are derivatives of beta- aminoethylbenzene which is structurally and pharmacologically related to amphetamine. (From Merck Index, 11th ed)Anti-Arrhythmia Agents: Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade.Sotalol: An adrenergic beta-antagonist that is used in the treatment of life-threatening arrhythmias.DNA Breaks: Interruptions in the sugar-phosphate backbone of DNA.Thiamine Monophosphate: Thiamine dihydrogen phosphate ester. The monophosphate ester of thiamine. Synonyms: monophosphothiamine; vitamin B1 monophosphate.Electrocardiography: Recording of the moment-to-moment electromotive forces of the HEART as projected onto various sites on the body's surface, delineated as a scalar function of time. The recording is monitored by a tracing on slow moving chart paper or by observing it on a cardioscope, which is a CATHODE RAY TUBE DISPLAY.Heart Block: Impaired conduction of cardiac impulse that can occur anywhere along the conduction pathway, such as between the SINOATRIAL NODE and the right atrium (SA block) or between atria and ventricles (AV block). Heart blocks can be classified by the duration, frequency, or completeness of conduction block. Reversibility depends on the degree of structural or functional defects.Atrioventricular Block: Impaired impulse conduction from HEART ATRIA to HEART VENTRICLES. AV block can mean delayed or completely blocked impulse conduction.Phosphoamino Acids: Amino acids that contain phosphorus as an integral part of the molecule.Benzamidines: Amidines substituted with a benzene group. Benzamidine and its derivatives are known as peptidase inhibitors.Diminazene: An effective trypanocidal agent.Topoisomerase I Inhibitors: Compounds that inhibit the activity of DNA TOPOISOMERASE I.DNA Repair: The reconstruction of a continuous two-stranded DNA molecule without mismatch from a molecule which contained damaged regions. The major repair mechanisms are excision repair, in which defective regions in one strand are excised and resynthesized using the complementary base pairing information in the intact strand; photoreactivation repair, in which the lethal and mutagenic effects of ultraviolet light are eliminated; and post-replication repair, in which the primary lesions are not repaired, but the gaps in one daughter duplex are filled in by incorporation of portions of the other (undamaged) daughter duplex. Excision repair and post-replication repair are sometimes referred to as "dark repair" because they do not require light.Sulfonamides: A group of compounds that contain the structure SO2NH2.Spinocerebellar Ataxias: A group of dominantly inherited, predominately late-onset, cerebellar ataxias which have been divided into multiple subtypes based on clinical features and genetic mapping. Progressive ataxia is a central feature of these conditions, and in certain subtypes POLYNEUROPATHY; DYSARTHRIA; visual loss; and other disorders may develop. (From Joynt, Clinical Neurology, 1997, Ch65, pp 12-17; J Neuropathol Exp Neurol 1998 Jun;57(6):531-43)Acetanilides: Compounds based on N-phenylacetamide, that are similar in structure to 2-PHENYLACETAMIDES. They are precursors of many other compounds. They were formerly used as ANALGESICS and ANTIPYRETICS, but often caused lethal METHEMOGLOBINEMIA.Camptothecin: An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA TOPOISOMERASES, TYPE I. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity.3-Mercaptopropionic Acid: An inhibitor of glutamate decarboxylase. It decreases the GAMMA-AMINOBUTYRIC ACID concentration in the brain, thereby causing convulsions.Dogs: The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065)Cnidarian Venoms: Venoms from jellyfish; CORALS; SEA ANEMONES; etc. They contain hemo-, cardio-, dermo- , and neuro-toxic substances and probably ENZYMES. They include palytoxin, sarcophine, and anthopleurine.Flunarizine: Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity. It is effective in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy.Delayed Rectifier Potassium Channels: A group of slow opening and closing voltage-gated potassium channels. Because of their delayed activation kinetics they play an important role in controlling ACTION POTENTIAL duration.DNA Topoisomerases, Type II: DNA TOPOISOMERASES that catalyze ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands. These enzymes bring about relaxation of the supercoiled DNA and resolution of a knotted circular DNA duplex.DNA Damage: Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS.Ventricular Premature Complexes: A type of cardiac arrhythmia with premature contractions of the HEART VENTRICLES. It is characterized by the premature QRS complex on ECG that is of abnormal shape and great duration (generally >129 msec). It is the most common form of all cardiac arrhythmias. Premature ventricular complexes have no clinical significance except in concurrence with heart diseases.Astemizole: Antihistamine drug now withdrawn from the market in many countries because of rare but potentially fatal side effects.Methoxamine: An alpha-1 adrenergic agonist that causes prolonged peripheral VASOCONSTRICTION.Thiamine: 3-((4-Amino-2-methyl-5-pyrimidinyl)methyl)-5-(2- hydroxyethyl)-4-methylthiazolium chloride.Phosphodiesterase Inhibitors: Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases.Arrhythmias, Cardiac: Any disturbances of the normal rhythmic beating of the heart or MYOCARDIAL CONTRACTION. Cardiac arrhythmias can be classified by the abnormalities in HEART RATE, disorders of electrical impulse generation, or impulse conduction.Potassium Channel Blockers: A class of drugs that act by inhibition of potassium efflux through cell membranes. Blockade of potassium channels prolongs the duration of ACTION POTENTIALS. They are used as ANTI-ARRHYTHMIA AGENTS and VASODILATOR AGENTS.Thiamine Pyrophosphate: The coenzyme form of Vitamin B1 present in many animal tissues. It is a required intermediate in the PYRUVATE DEHYDROGENASE COMPLEX and the KETOGLUTARATE DEHYDROGENASE COMPLEX.Drug-Related Side Effects and Adverse Reactions: Disorders that result from the intended use of PHARMACEUTICAL PREPARATIONS. Included in this heading are a broad variety of chemically-induced adverse conditions due to toxicity, DRUG INTERACTIONS, and metabolic effects of pharmaceuticals.Cisapride: A substituted benzamide used for its prokinetic properties. It is used in the management of gastroesophageal reflux disease, functional dyspepsia, and other disorders associated with impaired gastrointestinal motility. (Martindale The Extra Pharmacopoeia, 31st ed)Magnesium Sulfate: A small colorless crystal used as an anticonvulsant, a cathartic, and an electrolyte replenisher in the treatment of pre-eclampsia and eclampsia. It causes direct inhibition of action potentials in myometrial muscle cells. Excitation and contraction are uncoupled, which decreases the frequency and force of contractions. (From AMA Drug Evaluations Annual, 1992, p1083)Chromans: Benzopyrans saturated in the 2 and 3 positions.Indenes: A family of fused-ring hydrocarbons isolated from coal tar that act as intermediates in various chemical reactions and are used in the production of coumarone-indene resins.Topoisomerase Inhibitors: Compounds that inhibit the activity of DNA TOPOISOMERASES.Sumoylation: A type of POST-TRANSLATIONAL PROTEIN MODIFICATION by SMALL UBIQUITIN-RELATED MODIFIER PROTEINS (also known as SUMO proteins).Bradycardia: Cardiac arrhythmias that are characterized by excessively slow HEART RATE, usually below 50 beats per minute in human adults. They can be classified broadly into SINOATRIAL NODE dysfunction and ATRIOVENTRICULAR BLOCK.Thymidine Monophosphate: 5-Thymidylic acid. A thymine nucleotide containing one phosphate group esterified to the deoxyribose moiety.Ether-A-Go-Go Potassium Channels: A family of voltage-gated potassium channels that are characterized by long N-terminal and C-terminal intracellular tails. They are named from the Drosophila protein whose mutation causes abnormal leg shaking under ether anesthesia. Their activation kinetics are dependent on extracellular MAGNESIUM and PROTON concentration.Drug Evaluation, Preclinical: Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications.Action Potentials: Abrupt changes in the membrane potential that sweep along the CELL MEMBRANE of excitable cells in response to excitation stimuli.Heart Conduction System: An impulse-conducting system composed of modified cardiac muscle, having the power of spontaneous rhythmicity and conduction more highly developed than the rest of the heart.Sulfur Compounds: Inorganic or organic compounds that contain sulfur as an integral part of the molecule.Mexiletine: Antiarrhythmic agent pharmacologically similar to LIDOCAINE. It may have some anticonvulsant properties.DNA-(Apurinic or Apyrimidinic Site) Lyase: A DNA repair enzyme that catalyses the excision of ribose residues at apurinic and apyrimidinic DNA sites that can result from the action of DNA GLYCOSYLASES. The enzyme catalyzes a beta-elimination reaction in which the C-O-P bond 3' to the apurinic or apyrimidinic site in DNA is broken, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate. This enzyme was previously listed under EC 188.8.131.52.Rabbits: The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.Electrophysiologic Techniques, Cardiac: Methods to induce and measure electrical activities at specific sites in the heart to diagnose and treat problems with the heart's electrical system.Pentamidine: Antiprotozoal agent effective in trypanosomiasis, leishmaniasis, and some fungal infections; used in treatment of PNEUMOCYSTIS pneumonia in HIV-infected patients. It may cause diabetes mellitus, central nervous system damage, and other toxic effects.DNA-Binding Proteins: Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.DNA Adducts: The products of chemical reactions that result in the addition of extraneous chemical groups to DNA.Potassium Channels, Voltage-Gated: Potassium channel whose permeability to ions is extremely sensitive to the transmembrane potential difference. The opening of these channels is induced by the membrane depolarization of the ACTION POTENTIAL.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Quinidine: An optical isomer of quinine, extracted from the bark of the CHINCHONA tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular ACTION POTENTIALS, and decreases automaticity. Quinidine also blocks muscarinic and alpha-adrenergic neurotransmission.Furans: Compounds with a 5-membered ring of four carbons and an oxygen. They are aromatic heterocycles. The reduced form is tetrahydrofuran.DNA, Single-Stranded: A single chain of deoxyribonucleotides that occurs in some bacteria and viruses. It usually exists as a covalently closed circle.Transketolase: An enzyme of the transferase class that catalyzes the conversion of sedoheptulose 7-phosphate and D-glyceraldehyde 3-phosphate to D-ribose 5-phosphate and D-xylulose 5-phosphate in the PENTOSE PHOSPHATE PATHWAY. (Dorland, 27th ed) EC 184.108.40.206.Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.Patents as Topic: Exclusive legal rights or privileges applied to inventions, plants, etc.Tetracyclines: Closely congeneric derivatives of the polycyclic naphthacenecarboxamide. (Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed, p1117)Biomimetics: An interdisciplinary field in materials science, ENGINEERING, and BIOLOGY, studying the use of biological principles for synthesis or fabrication of BIOMIMETIC MATERIALS.Heart Rate: The number of times the HEART VENTRICLES contract per unit of time, usually per minute.Quaternary Ammonium Compounds: Derivatives of ammonium compounds, NH4+ Y-, in which all four of the hydrogens bonded to nitrogen have been replaced with hydrocarbyl groups. These are distinguished from IMINES which are RN=CR2.DNA Breaks, Double-Stranded: Interruptions in the sugar-phosphate backbone of DNA, across both strands adjacently.Polyneuropathies: Diseases of multiple peripheral nerves simultaneously. Polyneuropathies usually are characterized by symmetrical, bilateral distal motor and sensory impairment with a graded increase in severity distally. The pathological processes affecting peripheral nerves include degeneration of the axon, myelin or both. The various forms of polyneuropathy are categorized by the type of nerve affected (e.g., sensory, motor, or autonomic), by the distribution of nerve injury (e.g., distal vs. proximal), by nerve component primarily affected (e.g., demyelinating vs. axonal), by etiology, or by pattern of inheritance.Alkylation: The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group.Disease Models, Animal: Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.Cell Extracts: Preparations of cell constituents or subcellular materials, isolates, or substances.NAV1.5 Voltage-Gated Sodium Channel: A voltage-gated sodium channel subtype that mediates the sodium ion PERMEABILITY of CARDIOMYOCYTES. Defects in the SCN5A gene, which codes for the alpha subunit of this sodium channel, are associated with a variety of CARDIAC DISEASES that result from loss of sodium channel function.Amiodarone: An antianginal and class III antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting POTASSIUM CHANNELS and VOLTAGE-GATED SODIUM CHANNELS. There is a resulting decrease in heart rate and in vascular resistance.Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.DNA Ligases: Poly(deoxyribonucleotide):poly(deoxyribonucleotide)ligases. Enzymes that catalyze the joining of preformed deoxyribonucleotides in phosphodiester linkage during genetic processes during repair of a single-stranded break in duplex DNA. The class includes both EC 220.127.116.11 (ATP) and EC 18.104.22.168 (NAD).Sodium Channel Blockers: A class of drugs that act by inhibition of sodium influx through cell membranes. Blockade of sodium channels slows the rate and amplitude of initial rapid depolarization, reduces cell excitability, and reduces conduction velocity.Pregnenediones: Unsaturated pregnane derivatives containing two keto groups on side chains or ring structures.Purkinje Fibers: Modified cardiac muscle fibers composing the terminal portion of the heart conduction system.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.EstersLidocaine: A local anesthetic and cardiac depressant used as an antiarrhythmia agent. Its actions are more intense and its effects more prolonged than those of PROCAINE but its duration of action is shorter than that of BUPIVACAINE or PRILOCAINE.Syncope: A transient loss of consciousness and postural tone caused by diminished blood flow to the brain (i.e., BRAIN ISCHEMIA). Presyncope refers to the sensation of lightheadedness and loss of strength that precedes a syncopal event or accompanies an incomplete syncope. (From Adams et al., Principles of Neurology, 6th ed, pp367-9)Sodium Channels: Ion channels that specifically allow the passage of SODIUM ions. A variety of specific sodium channel subtypes are involved in serving specialized functions such as neuronal signaling, CARDIAC MUSCLE contraction, and KIDNEY function.Aza CompoundsSurface Plasmon Resonance: A biosensing technique in which biomolecules capable of binding to specific analytes or ligands are first immobilized on one side of a metallic film. Light is then focused on the opposite side of the film to excite the surface plasmons, that is, the oscillations of free electrons propagating along the film's surface. The refractive index of light reflecting off this surface is measured. When the immobilized biomolecules are bound by their ligands, an alteration in surface plasmons on the opposite side of the film is created which is directly proportional to the change in bound, or adsorbed, mass. Binding is measured by changes in the refractive index. The technique is used to study biomolecular interactions, such as antigen-antibody binding.Rats, Transgenic: Laboratory rats that have been produced from a genetically manipulated rat EGG or rat EMBRYO, MAMMALIAN. They contain genes from another species.High-Throughput Screening Assays: Rapid methods of measuring the effects of an agent in a biological or chemical assay. The assay usually involves some form of automation or a way to conduct multiple assays at the same time using sample arrays.Heart: The hollow, muscular organ that maintains the circulation of the blood.Heart Ventricles: The lower right and left chambers of the heart. The right ventricle pumps venous BLOOD into the LUNGS and the left ventricle pumps oxygenated blood into the systemic arterial circulation.Verapamil: A calcium channel blocker that is a class IV anti-arrhythmia agent.DNA Repair Enzymes: Enzymes that are involved in the reconstruction of a continuous two-stranded DNA molecule without mismatch from a molecule, which contained damaged regions.Isoquinolines: A group of compounds with the heterocyclic ring structure of benzo(c)pyridine. The ring structure is characteristic of the group of opium alkaloids such as papaverine. (From Stedman, 25th ed)Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures.Topotecan: An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA TOPOISOMERASES, TYPE I.Endonucleases: Enzymes that catalyze the hydrolysis of the internal bonds and thereby the formation of polynucleotides or oligonucleotides from ribo- or deoxyribonucleotide chains. EC 3.1.-.Nucleic Acid Synthesis Inhibitors: Compounds that inhibit cell production of DNA or RNA.Etoposide: A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.Amyotrophic Lateral Sclerosis: A degenerative disorder affecting upper MOTOR NEURONS in the brain and lower motor neurons in the brain stem and SPINAL CORD. Disease onset is usually after the age of 50 and the process is usually fatal within 3 to 6 years. Clinical manifestations include progressive weakness, atrophy, FASCICULATION, hyperreflexia, DYSARTHRIA, dysphagia, and eventual paralysis of respiratory function. Pathologic features include the replacement of motor neurons with fibrous ASTROCYTES and atrophy of anterior SPINAL NERVE ROOTS and corticospinal tracts. (From Adams et al., Principles of Neurology, 6th ed, pp1089-94)Biotinylation: Incorporation of biotinyl groups into molecules.Vertebrates: Animals having a vertebral column, members of the phylum Chordata, subphylum Craniata comprising mammals, birds, reptiles, amphibians, and fishes.Time Factors: Elements of limited time intervals, contributing to particular results or situations.DNA: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).Piperidines: A family of hexahydropyridines.Catalysis: The facilitation of a chemical reaction by material (catalyst) that is not consumed by the reaction.Models, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Ventricular Function: The hemodynamic and electrophysiological action of the HEART VENTRICLES.Cell Nucleolus: Within most types of eukaryotic CELL NUCLEUS, a distinct region, not delimited by a membrane, in which some species of rRNA (RNA, RIBOSOMAL) are synthesized and assembled into ribonucleoprotein subunits of ribosomes. In the nucleolus rRNA is transcribed from a nucleolar organizer, i.e., a group of tandemly repeated chromosomal genes which encode rRNA and which are transcribed by RNA polymerase I. (Singleton & Sainsbury, Dictionary of Microbiology & Molecular Biology, 2d ed)Death, Sudden, Cardiac: Unexpected rapid natural death due to cardiovascular collapse within one hour of initial symptoms. It is usually caused by the worsening of existing heart diseases. The sudden onset of symptoms, such as CHEST PAIN and CARDIAC ARRHYTHMIAS, particularly VENTRICULAR TACHYCARDIA, can lead to the loss of consciousness and cardiac arrest followed by biological death. (from Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed., 2005)Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body.Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures.Oligonucleotides: Polymers made up of a few (2-20) nucleotides. In molecular genetics, they refer to a short sequence synthesized to match a region where a mutation is known to occur, and then used as a probe (OLIGONUCLEOTIDE PROBES). (Dorland, 28th ed)Disease Susceptibility: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the individual more than usually susceptible to certain diseases.Antigens, Neoplasm: Proteins, glycoprotein, or lipoprotein moieties on surfaces of tumor cells that are usually identified by monoclonal antibodies. Many of these are of either embryonic or viral origin.Benzenesulfonates: Organic salts and esters of benzenesulfonic acid.Cells, Cultured: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.Epistasis, Genetic: A form of gene interaction whereby the expression of one gene interferes with or masks the expression of a different gene or genes. Genes whose expression interferes with or masks the effects of other genes are said to be epistatic to the effected genes. Genes whose expression is affected (blocked or masked) are hypostatic to the interfering genes.Biotin: A water-soluble, enzyme co-factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.PiperazinesDNA-Activated Protein Kinase: A serine-threonine protein kinase that, when activated by DNA, phosphorylates several DNA-binding protein substrates including the TUMOR SUPPRESSOR PROTEIN P53 and a variety of TRANSCRIPTION FACTORS.Ataxia Telangiectasia: An autosomal recessive inherited disorder characterized by choreoathetosis beginning in childhood, progressive CEREBELLAR ATAXIA; TELANGIECTASIS of CONJUNCTIVA and SKIN; DYSARTHRIA; B- and T-cell immunodeficiency, and RADIOSENSITIVITY to IONIZING RADIATION. Affected individuals are prone to recurrent sinobronchopulmonary infections, lymphoreticular neoplasms, and other malignancies. Serum ALPHA-FETOPROTEINS are usually elevated. (Menkes, Textbook of Child Neurology, 5th ed, p688) The gene for this disorder (ATM) encodes a cell cycle checkpoint protein kinase and has been mapped to chromosome 11 (11q22-q23).Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.Electrophysiology: The study of the generation and behavior of electrical charges in living organisms particularly the nervous system and the effects of electricity on living organisms.Kinetics: The rate dynamics in chemical or physical systems.Calcium Channels, L-Type: Long-lasting voltage-gated CALCIUM CHANNELS found in both excitable and nonexcitable tissue. They are responsible for normal myocardial and vascular smooth muscle contractility. Five subunits (alpha-1, alpha-2, beta, gamma, and delta) make up the L-type channel. The alpha-1 subunit is the binding site for calcium-based antagonists. Dihydropyridine-based calcium antagonists are used as markers for these binding sites.Potassium Channels: Cell membrane glycoproteins that are selectively permeable to potassium ions. At least eight major groups of K channels exist and they are made up of dozens of different subunits.Mutant Proteins: Proteins produced from GENES that have acquired MUTATIONS.Protein Interaction Domains and Motifs: Protein modules with conserved ligand-binding surfaces which mediate specific interaction functions in SIGNAL TRANSDUCTION PATHWAYS and the specific BINDING SITES of their cognate protein LIGANDS.Adrenergic beta-Antagonists: Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.Poly(ADP-ribose) Polymerases: Enzymes that catalyze the transfer of multiple ADP-RIBOSE groups from nicotinamide-adenine dinucleotide (NAD) onto protein targets, thus building up a linear or branched homopolymer of repeating ADP-ribose units i.e., POLY ADENOSINE DIPHOSPHATE RIBOSE.Mice, Knockout: Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.DNA, Fungal: Deoxyribonucleic acid that makes up the genetic material of fungi.Pyridines: Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Adrenergic alpha-Agonists: Drugs that selectively bind to and activate alpha adrenergic receptors.Tachycardia, Ventricular: An abnormally rapid ventricular rhythm usually in excess of 150 beats per minute. It is generated within the ventricle below the BUNDLE OF HIS, either as autonomic impulse formation or reentrant impulse conduction. Depending on the etiology, onset of ventricular tachycardia can be paroxysmal (sudden) or nonparoxysmal, its wide QRS complexes can be uniform or polymorphic, and the ventricular beating may be independent of the atrial beating (AV dissociation).Catalytic Domain: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction.Cell Line, Tumor: A cell line derived from cultured tumor cells.Myocytes, Cardiac: Striated muscle cells found in the heart. They are derived from cardiac myoblasts (MYOBLASTS, CARDIAC).Cell Line: Established cell cultures that have the potential to propagate indefinitely.Cardiac Pacing, Artificial: Regulation of the rate of contraction of the heart muscles by an artificial pacemaker.Models, Cardiovascular: Theoretical representations that simulate the behavior or activity of the cardiovascular system, processes, or phenomena; includes the use of mathematical equations, computers and other electronic equipment.Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.Crystallography, X-Ray: The study of crystal structure using X-RAY DIFFRACTION techniques. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Models, Animal: Non-human animals, selected because of specific characteristics, for use in experimental research, teaching, or testing.Phenylephrine: An alpha-1 adrenergic agonist used as a mydriatic, nasal decongestant, and cardiotonic agent.Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds.Proteins: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.Multienzyme Complexes: Systems of enzymes which function sequentially by catalyzing consecutive reactions linked by common metabolic intermediates. They may involve simply a transfer of water molecules or hydrogen atoms and may be associated with large supramolecular structures such as MITOCHONDRIA or RIBOSOMES.Isoproterenol: Isopropyl analog of EPINEPHRINE; beta-sympathomimetic that acts on the heart, bronchi, skeletal muscle, alimentary tract, etc. It is used mainly as bronchodilator and heart stimulant.Risk Assessment: The qualitative or quantitative estimation of the likelihood of adverse effects that may result from exposure to specified health hazards or from the absence of beneficial influences. (Last, Dictionary of Epidemiology, 1988)Saccharomyces cerevisiae: A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement.Amino Acid Motifs: Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a CONSERVED SEQUENCE which can be represented by a CONSENSUS SEQUENCE.Perfusion: Treatment process involving the injection of fluid into an organ or tissue.Phosphotyrosine: An amino acid that occurs in endogenous proteins. Tyrosine phosphorylation and dephosphorylation plays a role in cellular signal transduction and possibly in cell growth control and carcinogenesis.Chickens: Common name for the species Gallus gallus, the domestic fowl, in the family Phasianidae, order GALLIFORMES. It is descended from the red jungle fowl of SOUTHEAST ASIA.Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from GLYCINE or THREONINE. It is involved in the biosynthesis of PURINES; PYRIMIDINES; and other amino acids.Manganese: A trace element with atomic symbol Mn, atomic number 25, and atomic weight 54.94. It is concentrated in cell mitochondria, mostly in the pituitary gland, liver, pancreas, kidney, and bone, influences the synthesis of mucopolysaccharides, stimulates hepatic synthesis of cholesterol and fatty acids, and is a cofactor in many enzymes, including arginase and alkaline phosphatase in the liver. (From AMA Drug Evaluations Annual 1992, p2035)Models, Chemical: Theoretical representations that simulate the behavior or activity of chemical processes or phenomena; includes the use of mathematical equations, computers, and other electronic equipment.Genetic Complementation Test: A test used to determine whether or not complementation (compensation in the form of dominance) will occur in a cell with a given mutant phenotype when another mutant genome, encoding the same mutant phenotype, is introduced into that cell.Chronic Disease: Diseases which have one or more of the following characteristics: they are permanent, leave residual disability, are caused by nonreversible pathological alteration, require special training of the patient for rehabilitation, or may be expected to require a long period of supervision, observation, or care. (Dictionary of Health Services Management, 2d ed)Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.DNA, Ribosomal: DNA sequences encoding RIBOSOMAL RNA and the segments of DNA separating the individual ribosomal RNA genes, referred to as RIBOSOMAL SPACER DNA.Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.Predictive Value of Tests: In screening and diagnostic tests, the probability that a person with a positive test is a true positive (i.e., has the disease), is referred to as the predictive value of a positive test; whereas, the predictive value of a negative test is the probability that the person with a negative test does not have the disease. Predictive value is related to the sensitivity and specificity of the test.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.Potassium: An element in the alkali group of metals with an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the WATER-ELECTROLYTE BALANCE.Cations, Divalent: Positively charged atoms, radicals or groups of atoms with a valence of plus 2, which travel to the cathode or negative pole during electrolysis.Hydrogen-Ion Concentration: The normality of a solution with respect to HYDROGEN ions; H+. It is related to acidity measurements in most cases by pH = log 1/2[1/(H+)], where (H+) is the hydrogen ion concentration in gram equivalents per liter of solution. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)Astrocytes: A class of large neuroglial (macroglial) cells in the central nervous system - the largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the BLOOD-BRAIN BARRIER. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with MICROGLIA) respond to injury.Risk Factors: An aspect of personal behavior or lifestyle, environmental exposure, or inborn or inherited characteristic, which, on the basis of epidemiologic evidence, is known to be associated with a health-related condition considered important to prevent.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.Sensitivity and Specificity: Binary classification measures to assess test results. Sensitivity or recall rate is the proportion of true positives. Specificity is the probability of correctly determining the absence of a condition. (From Last, Dictionary of Epidemiology, 2d ed)Saccharomyces cerevisiae Proteins: Proteins obtained from the species SACCHAROMYCES CEREVISIAE. The function of specific proteins from this organism are the subject of intense scientific interest and have been used to derive basic understanding of the functioning similar proteins in higher eukaryotes.Islets of Langerhans: Irregular microscopic structures consisting of cords of endocrine cells that are scattered throughout the PANCREAS among the exocrine acini. Each islet is surrounded by connective tissue fibers and penetrated by a network of capillaries. There are four major cell types. The most abundant beta cells (50-80%) secrete INSULIN. Alpha cells (5-20%) secrete GLUCAGON. PP cells (10-35%) secrete PANCREATIC POLYPEPTIDE. Delta cells (~5%) secrete SOMATOSTATIN.Models, Biological: Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.Chromatography, High Pressure Liquid: Liquid chromatographic techniques which feature high inlet pressures, high sensitivity, and high speed.Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water.Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.Embryo, Mammalian: The entity of a developing mammal (MAMMALS), generally from the cleavage of a ZYGOTE to the end of embryonic differentiation of basic structures. For the human embryo, this represents the first two months of intrauterine development preceding the stages of the FETUS.Patch-Clamp Techniques: An electrophysiologic technique for studying cells, cell membranes, and occasionally isolated organelles. All patch-clamp methods rely on a very high-resistance seal between a micropipette and a membrane; the seal is usually attained by gentle suction. The four most common variants include on-cell patch, inside-out patch, outside-out patch, and whole-cell clamp. Patch-clamp methods are commonly used to voltage clamp, that is control the voltage across the membrane and measure current flow, but current-clamp methods, in which the current is controlled and the voltage is measured, are also used.Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.Risk: The probability that an event will occur. It encompasses a variety of measures of the probability of a generally unfavorable outcome.Guinea Pigs: A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research.DNA, Mitochondrial: Double-stranded DNA of MITOCHONDRIA. In eukaryotes, the mitochondrial GENOME is circular and codes for ribosomal RNAs, transfer RNAs, and about 10 proteins.Models, Genetic: Theoretical representations that simulate the behavior or activity of genetic processes or phenomena. They include the use of mathematical equations, computers, and other electronic equipment.Spectrometry, Fluorescence: Measurement of the intensity and quality of fluorescence.
465(7295): p. 223-6. Roeber, S., et al., TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD. Acta ... McKeen, H.D., et al., FKBPL regulates estrogen receptor signaling and determines response to endocrine therapy. Cancer Res, ... 116(2): p. 215-20 Chanson, J.B., et al., TDP43-positive intraneuronal inclusions in a patient with motor neuron disease and ... Tan, C.F., et al., Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado-Joseph ...
It was also reported to regulate alternate splicing of the CFTR gene and the apoA-II gene. In spinal motor neurons TDP-43 has ... In addition, this protein regulates alternate splicing of the CFTR gene. In particular, TDP-43 is a splicing factor binding to ... FTLD-TDP, previously referred to as FTLD-U) and in Amyotrophic lateral sclerosis (ALS). Elevated levels of the TDP-43 protein ... TDP-43 has been shown to bind both DNA and RNA and have multiple functions in transcriptional repression, pre-mRNA splicing and ...
Dewey CM, Cenik B, Sephton CF, Dries DR, Mayer P, Good SK, Johnson BA, Herz J, Yu G (March 2011). "TDP-43 is directed to stress ... Pare JM, Tahbaz N, López-Orozco J, LaPointe P, Lasko P, Hobman TC (July 2009). "Hsp90 regulates the function of argonaute 2 and ... Colombrita C, Zennaro E, Fallini C, Weber M, Sommacal A, Buratti E, Silani V, Ratti A (November 2009). "TDP-43 is recruited to ... Leung AK, Vyas S, Rood JE, Bhutkar A, Sharp PA, Chang P (May 2011). "Poly(ADP-ribose) regulates stress responses and microRNA ...
Genetics of amyotrophic lateral sclerosis
The TDP-43 protein, coded for by the TARDBP gene, is responsible for regulation of RNA expression. The discovery of mutations ... A 2016 paper proposed that SOD1 maturation and proteins regulating intracellular copper levels are potential therapeutic ... SOD1 and TDP-43 mutations may play a role in causing mitochondria dysfunction. Increased markers of oxidative stress have been ... possibly originating in a TDP-43 mutation.) However authors cautioned against assuming a causal role of microRNA dysregulation ...
Epigenetics of neurodegenerative diseases
"Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease." J ... Dewey CM, Cenik B, Sephton CF, Johnson BA, Herz J, Yu G. "TDP-43 aggregation in neurodegeneration: are stress granules the key ... "HDAC2 negatively regulates memory formation and synaptic plasticity." Nature 459.7243 (2009): 55-60. Kilgore M, Miller CA, Fass ... Expression of CREB, an activity-dependent transcription factor involved in regulating BDNF among many other genes, has also ...
Cyclin F differs from other cyclins by its ability to monitor and regulate cell cycle without the need for cyclin-dependent ... It was found that certain CCNF mutations caused increased ubiquitination of TDP-43 protein in cells, which is a major feature ... Kong M, Barnes EA, Ollendorff V, Donoghue DJ (March 2000). "Cyclin F regulates the nuclear localization of cyclin B1 through a ... Moreover, cyclin F located at the centrosomes are needed to regulate levels of CP110, a protein involved in centrosome ...
In Drosophila melanogaster, the protein has been shown to define the vesicle release site by regulating the coupling distance ... Pathology involving TDP-43 is a result of the single nucleotide polymorphisms in both ALS and FTD. This gene has also been ... Lavi A, Sheinin A, Shapira R, Zelmanoff D, Ashery U (September 2014). "DOC2B and Munc13-1 differentially regulate neuronal ... Hartlage-Rübsamen M, Waniek A, Roßner S (February 2013). "Munc13 genotype regulates secretory amyloid precursor protein ...
He has also developed a series of compounds that potently and effectively inhibit TDP-43 aggregation in multiple neuronal ... This work prompted the concept that "regulated protein aggregation", which provides a theoretical framework for understanding ... TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue". PLoS ONE. 5 (10). doi: ... "Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity". Cell Reports. 15 (7): 1455- ...
Sklerosis lateral amiotrofik bahasa Indonesia, ensiklopedia bebas
"ALS and FTLD: two faces of TDP-43 proteinopathy". Institute for Medical Research and Occupational Health; Liscic RM, Grinberg ... "Nerve growth factor regulates the firing patterns and synaptic composition of motoneurons". Departamento de Fisiología y ... Pada tahun 2009, dilaporkan bahwa model tikus dengan ekspresi genetik termutasi pada TDP-43 (bahasa Inggris: TAR DNA-binding ... "Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching". ...
Mir-663 microRNA precursor family
MicroRNAs function to regulate the expression levels of other genes by several mechanisms. miR-663 has been identified as a ... Buratti, E.; De Conti, L.; Stuani, C.; Romano, M.; Baralle, M.; Baralle, F. (2010). "Nuclear factor TDP-43 can affect selected ... Liu, Z. Y.; Zhang, G. L.; Wang, M. M.; Xiong, Y. N.; Cui, H. Q. (2011). "MicroRNA-663 targets TGFB1 and regulates lung cancer ...
Exonic splicing silencer
The TDP-43 protein is responsible for physically silencing the exon splicing site once it is recruited by the exonic splicing ... ESSs have four general roles: inhibiting exon inclusion inhibiting intron retention regulating alternative 5' splice site usage ... Pozzoli, U.; Sironi, M. (2005-05-18). "Silencers regulate both constitutive and alternative splicing events in mammals". ... TDP-43 is a DNA binding protein and repressor, it binds to the TG repeat to cause exon 9 skipping. The role of the T tracts is ...
Irimura S, Kitamura K, Kato N, Saiki K, Takeuchi A, Matsuo M, Nishio H, Lee MJ (2009). "HnRNP C1/C2 may regulate exon 7 ... Bose JK, Wang IF, Hung L, Tarn WY, Shen CK (October 2008). "TDP-43 overexpression enhances exon 7 inclusion during the survival ... 283 (43): 28852-9. doi:10.1074/jbc.M805376200. PMC 2661999 . PMID 18703504. Hauke J, Riessland M, Lunke S, Eyüpoglu IY, Blümcke ...
It is currently the most common demonstrated mutation related to ALS - far more common than SOD1 or TDP-43. While different ... A recent study provided the first experimental evidence to confirm this: C9ORF72 was found to regulate endosomal trafficking ... Certain pathology in FTD caused by the C9orf72 mutation can also include: TDP-43 in all C9 carriers Ubiquitin-binding protein ... regulates endosomal trafficking". Human Molecular Genetics. 23: 3579-3595. doi:10.1093/hmg/ddu068. PMC 4049310 . PMID 24549040 ...
Mechanistic target of rapamycin
Long X, Ortiz-Vega S, Lin Y, Avruch J (June 2005). "Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino ... Caccamo A, Majumder S, Deng JJ, Bai Y, Thornton FB, Oddo S (October 2009). "Rapamycin rescues TDP-43 mislocalization and the ... Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (April 2005). "Rheb binds and regulates the mTOR kinase". Current Biology. 15 ... Jia K, Chen D, Riddle DL (August 2004). "The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans ...
Ito D, Suzuki N (2011). "Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS". ... certain gene-regulating proteins inappropriately aggregate in the cytoplasm, and thus are unable to perform their normal tasks ... TDP-43). In all of these instances, an aberrant form of the protein itself appears to be the pathogenic agent. In some cases, ... 43 (3): 552-557. doi:10.1016/j.nbd.2011.05.001. PMC 3430516 . PMID 21600984. Kordower JH, et al. (2008). "Lewy body-like ...
Amyotrophic lateral sclerosis research
The TDP-43 transgenic mouse model was also used for ALS studies and it shows similar results to the SOD1 expression, which ... and they found that the functional genes and the ER stress regulating genes of the mitochondria were reduced in SOD-1 patients ... have made many other transgenic mouse models that uses different promoter to compare their phenotype and progression of TDP-43 ...
More recently, TDP-43 and FUS protein aggregates have been implicated in some cases of the disease, and a mutation in ... Turner PR, O'Connor K, Tate WP, Abraham WC (May 2003). "Roles of amyloid precursor protein and its fragments in regulating ... This pathway controls the activation of caspase-9 by regulating the release of cytochrome c from the mitochondrial ... Plaques are made up of small peptides, 39-43 amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta- ...
Biosynthesis of doxorubicin
Dnr S, daunosamine glycosyltransferase catalyzes the addition of the TDP activated glycoside, L-daunosamine-TDP to ε- ... their synthesis is tightly regulated. Doxorubicin is synthesized by a specialized polyketide synthase. The initial event in DXR ... rhodomycinone to give rhodomycin D (Figure 2). The release of TDP drives the reaction forward. The enzyme has sequence ... 4 (6): 433-43. doi:10.1016/S1074-5521(97)90195-2. PMID 9224566. Wohlert SE, Wendt-Pienkowski E, Bao W, Hutchinson CR (2001). " ...
More recently, TDP-43 and FUS protein aggregates have been implicated in some cases of the disease, and a mutation in ... Turner PR, O'Connor K, Tate WP, Abraham WC (May 2003). "Roles of amyloid precursor protein and its fragments in regulating ... This pathway controls the activation of caspase-9 by regulating the release of cytochrome c from the mitochondrial ... This suggests that there could be therapeutic value to PRP-1. ...
Etiogenic factors present in the cerebrospinal fluid from amyotrophic lateral sclerosis patients induce predominantly pro...
Ding X, Ma M, Teng J, Teng RKF, Zhou S, Yin J, Fonkem E, Huang JH, Wu E, Wang X. Exposure to ALS-FTD-CSF generates TDP-43 ... Microglial activation is temporally regulated. a-a" The Iba-1-positive microglial cells in response to ALS-CSF at 12, 24, and ... ALS-CSF regulates the synthesis and release of the cytokines. The analysis of mRNA expression uponALS-CSF exposure revealed an ... Swarup V, Phaneuf D, Dupré N, Petri S, Strong M, Kriz J, Julien J-P. Deregulation of TDP-43 in amyotrophic lateral sclerosis ...
JCI - TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets
Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons, but also in glucose intolerance due ... Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion ... Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in ... TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets. ...
JCI - TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets
C) Immunohistochemistry of the hypothalamus in Tardbpfl/fl, CKO-TDP, AAV-Control, and AAV-KO mice with an anti-TDP-43 antibody ... CKO-TDP). In Tardbpfl/fl and CKO-TDP mice without AAV injection, the IPGTT and insulin test were performed in 6-week-old male ... CKO-TDP). Pancreatic islets and brains of male AAV-KO ROSA26 mice and CKO-TDP ROSA26 mice were analyzed at 8-10 weeks of age. ... Immunofluorescence of the islets in Tardbpfl/fl and CKO-TDP mice. Scale bars: 10 μm. (B) Ratio of TDP-43-positive total cells ( ...
TDP-43 is a developmentally regulated protein essential for early embryonic development
TDP-43 is a DNA/RNA-binding protein implicated in multiple steps of transcriptional and post-transcriptional regulation of gene ... TDP-43 is a developmentally regulated protein essential for early embryonic development J Biol Chem. 2010 Feb 26;285(9):6826-34 ... TDP-43 is detected in spinal cord progenitors and in differentiated motor neurons as well as in the dorsal root ganglia at ... TDP-43 is a DNA/RNA-binding protein implicated in multiple steps of transcriptional and post-transcriptional regulation of gene ...
If these cells lack the TDP-43 protein, they not... ... The TDP-43 protein regulates the activity of scavenger cells. ... Article: TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss, Lawrence Rajendran et al., ... In this case, as well, they switched off TDP-43 in microglia and observed once more that the cells efficiently eliminated the β ... This is due to the fact that the lack of TDP-43 protein in microglia led to an increased scavenging activity, called ...
Search results | ALZFORUM
MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis. - PubMed - NCBI
However, TDP-43 pathology is common to over 95% of amyotrophic lateral sclerosis cases, suggesting that abnormalities of TDP-43 ... MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis.. MacNair L1, Xiao S2, ... It is our hypothesis that a loss of TDP-43 from the nucleus of affected motor neurons in amyotrophic lateral sclerosis will ... Both of these identified genes, DDX58 and MTHFSD, are RNA-binding proteins, and we show that TDP-43 binds to their respective ...
RNA-Processing Protein TDP-43 Regulates FOXO-Dependent Protein Quality Control in Stress Response | proLékárníky.cz
C. elegans TDP-1 regulates lifespan and proteotoxicity through DAF-16. C. elegans lacking its sole TDP-43 ortholog, TDP-1, ... mutants and WT controls indicates that there are more genes down-regulated than up-regulated in tdp-1(ok803lf) mutants (Figure ... The WT N2 C. elegans and mutant strains RB929 [tdp-1(ok803)], CF1038 [daf-16(mu86)], CB1370 [daf-2(e1370)], IW417 [tdp-1(ok803 ... The results indicated that most of the tested DAF-16 target genes are significantly up-regulated in tdp-1(ok803lf) mutant C. ...
Autophagy and apoptosis dysfunction in neurodegenerative disorders. - PubMed - NCBI
SMN complex member Gemin3 self-interacts and has a functional relationship with ALS-linked proteins TDP-43, FUS and Sod1 |...
C9orf72, SOD1, TDP-43 and FUS are ranked as the four major genes causing familial ALS. Accumulating evidence has revealed a ... Focusing on motor behaviour, muscle mass and survival, we show that disruption of either TBPH/TDP-43 or Caz/FUS enhance defects ... Both RBPs were later shown to bind to predominantly UG-rich sequences in RNA transcripts, regulating the expression and ... We note that neither haploinsufficiency (TBPHΔ23) nor RNAi-induced knockdown (TBPH-RNAi) of TBPH, the Drosophila TDP-43 ...
Molecular Neurodegeneration | Full text | Endogenous TDP-43, but not FUS, contributes to stress granule assembly via G3BP
TDP-43 (encoded by TARDBP) is an ALS-causative gene that we have previously implicated in the regulation of the core stress ... Here, we report that TDP-43 is required for proper SG dynamics, especially SG assembly as marked by the secondary aggregation ... We also demonstrate that endogenous TDP-43 and FUS do not have overlapping functions in this cellular process as SG initiation ... These data raise the possibility that disruptions of normal stress granule dynamics by loss of nuclear TDP-43 function may ...
Variable Tdp-43 cryptic exons between cell types | EurekAlert! Science News
If Tdp-43 is normal, it will repress the expression of a specific cryptic exon and produce a normal protein; however, when a ... Variable Tdp-43 cryptic exons between cell types International research team including the Korea Brain Research Institute found ... Recently, studies about Tdp-43 protein (Transactive response DNA binding protein 43 kDa, TARDBP), a major common cause of ... Tdp-43 Cryptic Exons Are Highly Variable between Cell Types (IMAGE) view more ...
Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism<...
We show that Tbc1d1, a gene known to mediate leanness and linked to obesity, is down-regulated in the absence of TDP-43. ... We show that Tbc1d1, a gene known to mediate leanness and linked to obesity, is down-regulated in the absence of TDP-43. ... We show that Tbc1d1, a gene known to mediate leanness and linked to obesity, is down-regulated in the absence of TDP-43. ... We show that Tbc1d1, a gene known to mediate leanness and linked to obesity, is down-regulated in the absence of TDP-43. ...
TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar...
... as also shown here for TDP43WT mice. Although PrP-TDP43A315T mice do not deposit TDP-43-positive NCIs or NIIs, ... TDP43WT Mice Display Neuropathology Reminiscent of FTLD/ALS.. One of the chief pathological findings in ALS and FTLD-TDP brains ... The NCIs in TDP43WT mice also contained phosphorylated and ubiquitinated forms of TDP-43; however, in many such inclusions, TDP ... S1). In none of the TDP43WT lines did TDP-43 expression exceed 1× endogenous TDP-43 expression. To increase transgene dose, we ...
ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS | PNAS
... further supporting TDP-43s role in regulating gene expression (17, 18). There is, however, growing evidence indicating that ... TDP43G298S, TDP43Q331K, and TDP43M337V), we showed that all three of these ALS-linked mutations exhibit longer protein half- ... Preferential ALS-Linked Mutant TDP43 Association with FUS/TLS.. Discovery of FUS/TLS, another ALS-linked gene product, in TDP- ... with TDP-43s role in RNA transcription and processing and complement a recent ultrastructural study showing that TDP-43 is ...
Overactive scavenger cells may cause neurodegeneration in Alzheimer's | EurekAlert! Science News
If these cells lack the TDP-43 protein, they not only remove Alzheimers plaques, but also synapses. This removal of synapses ... The TDP-43 protein regulates the activity of scavenger cells. In the next step, researchers used mice, which acted as a disease ... In this case, as well, they switched off TDP-43 in microglia and observed once more that the cells efficiently eliminated the β ... This is due to the fact that the lack of TDP-43 protein in microglia led to an increased scavenging activity, called ...
Thomas Montine | Stanford Medicine Profiles
The phosphatase calcineurin regulates pathological TDP-43 phosphorylation. Acta neuropathologica Liachko, N. F., Saxton, A. D ... FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post- ... Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models. To ... Lastly, calcineurin co-localizes with pTDP in degenerating areas of the central nervous system in subjects with FTLD-TDP and ...
Identification and characterization of ubiquitinylation sites in TAR DNA-binding protein of 43 kDa (TDP-43) Cell Biology
Pathological modifications of TDP-43 include proteolytic fragmentation, phosphorylation, and ubiquitinylation. A pathognomonic ... TDP-43) forms pathological aggregates in neurodegenerative diseases, particularly in certain forms of frontotemporal dementia ... TDP-43 C-terminal fragment (CTF) spanning amino acids 193-414 contains ... ... C9orf72-dependent lysosomal functions regulate epigenetic control of autophagy and lipid metabolism. ...
Repetitive Head Injury Syndrome: Background, Epidemiology, Functional Anatomy
55] TDP-43 is involved in regulating translation in mitochondrial RNA in the brain. It has been associated with the ... Cytosolic TDP-43 expression following axotomy is associated with caspase 3 activation in NFL-/- mice: support for a role for ... TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2010 Sep. 69(9): ... As in the case of tau, TDP-43 fibrillaries accumulate at anatomical points of geometric inflection in the brains of CTE ...
TDP-43/TARDBP Antibody (2E2-D3) (H00023435-M01): Novus Biologicals
Mouse Monoclonal Anti-TDP-43/TARDBP Antibody (2E2-D3) cited in 147 publications. Validated: WB, ELISA, ICC/IF, IHC, IHC-P, IP. ... UBE2E Ubiquitin-conjugating Enzymes and Ubiquitin Isopeptidase Y Regulate TDP-43 Protein Ubiquitination. J Biol Chem. 2014 May ... TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA. EMBO J. 2014 Nov 12 [PMID ... TDP-43/TARDBP Antibody (2E2-D3) Summary. Immunogen. TARDBP (AAH01487, 1 a.a. ~ 260 a.a) full length recombinant protein with ...
Multiplex SILAC Analysis of a Cellular TDP-43 Proteinopathy Model Reveals Protein Inclusions Associated with SUMOylation and...
2002) Rab11a and myosin Vb regulate recycling of the M4 muscarinic acetylcholine receptor. J. Neurosci. 22, 9776-9784 ... 6, A and B) indicated that TDP-S6-expressing cells had more TDP in the insoluble proteome compared with TDP-43-expressing cells ... and more dramatically with TDP-S6 overexpression (Fig. 4). TDP-S6 also displayed two short TDP-43-immunoreactive species (∼30 ... 3, A and B). The degree of TDP-S6 and TDP-43 enrichment in the insoluble fraction was also repeatable using a second ...
TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD | Science
The top 124 down-regulated/up-regulated genes in the Tdp-43 knockout cells were mostly restored to normal levels in the GTR1 ... N-TDP) to a well-characterized splicing repressor domain, replacing TDP-43s C-terminal fragment (C-TDP) (Fig. 2A). N-TDP ... Further evidence of Tdp-43s role in repressing cryptic exons comes from previous HITS-CLIP data that mapped Tdp-43s direct ... The discovery of TDP-43s role in repressing cryptic exons will advance our understanding of human diseases with TDP-43 ...
TARDBP gene: MedlinePlus Genetics
TDP-43). This protein is found within the cell nucleus in most tissues and is involved in many of the steps of protein ... The TARDBP gene provides instructions for making a protein called transactive response DNA binding protein 43 kDa ( ... to DNA and regulates an activity called transcription, which is the first step in the production of proteins from genes. This ... Changes to the TDP-43 protein cause the protein to misfold and form protein clumps (aggregates), which have been found in nerve ...
JCI - Volume 129, Issue 9
Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons, but also in glucose intolerance due ... Our results suggest that plasma LEAP2 is regulated by metabolic status: its levels increased with body mass and blood glucose ... Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion ... Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in ...
Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. | Broad Institute
TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ... The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease ... TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of ... Thus, TDP-43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43. ...
Proteintech - Wikipedia
465(7295): p. 223-6. Roeber, S., et al., TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD. Acta ... McKeen, H.D., et al., FKBPL regulates estrogen receptor signaling and determines response to endocrine therapy. Cancer Res, ... 116(2): p. 215-20 Chanson, J.B., et al., TDP43-positive intraneuronal inclusions in a patient with motor neuron disease and ... Tan, C.F., et al., Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado-Joseph ...
Structural determinants of the cellular localization and shuttling of TDP-43 | Journal of Cell Science
In addition to disrupting RNA binding (Buratti and Baralle, 2001), RRM-1 mutants fail to regulate alternative splicing (our ... TDP-43 comprises two RNA recognition motifs (RRMs) followed by a glycine-rich C-terminal domain. The presence of the RRMs is a ... TDP-43 shuttling was seen with GFP- or FLAG-tagged protein in HeLa and U2OS cell lines. These results confirmed that TDP-43 ... In fact, TDP-43 associates with hnRNP A isoforms (i.e. hnRNP A1 and hnRNP A2/B1) through this region specifically. The ...
A novel Drosophila model of TDP-43 proteinopathies: N-terminal sequences combined with the Q/N domain induce protein functional...
... but also in regulating TDP-43 folding, homotypic interaction, splicing functionality and cytoplasmic sequestration (Zhang et al ... The AggIn (Flag-TDP-Δ1-ΔC-RRM2F/L-12×Q/N) plasmid was generated by site-directed mutagenesis using the pcDNA5/FRT/TO-Flag-TDP- ... TDP wt; left-hand two lanes), Flag-tagged TDP-12×Q/N (middle two lanes) or AggIn (right-hand two lanes) in stable HEK293 cell ... Flag-TDP-Δ1-ΔC-RRM2F/L-12×Q/N) construct are identified along with their relative position in the wild-type human TDP-43 ...
Frontiers | Control of mRNA Translation in ALS Proteinopathy | Frontiers in Molecular Neuroscience
Both TDP-43 and FUS are found in RNA transport granules (Kanai et al., 2004; Elvira et al., 2006), and ALS-linked mutant TDP-43 ... 2016). Protein-RNA networks regulated by normal and ALS-associated mutant HNRNPA2B1 in the nervous system. Neuron 92, 780-795. ... FUS and TDP-43, as well as other ALS-related genes, have also a recognized role in the regulation of RNA metabolism, including ... In addition to TDP-43 and FUS, also hnRNP A2/B1 and hnRNP A1 (heterogeneous nuclear ribonucleoprotein A2/B1 and A1), two RBPs ...
Emanuele Buratti - Google Scholar Citations
Nuclear factor TDP‐43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. E Buratti, T D rk, E Zuccato, F Pagani ... TDP‐43 regulates its mRNA levels through a negative feedback loop. YM Ayala, L De Conti, SE Avenda o‐V zquez, A Dhir, M Romano ... Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene. PA Mercado, YM ... TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. J Sreedharan, IP Blair, VB Tripathi, X Hu, C Vance, B ...
Stress Granules and ALS: A Case of Causation or Correlation? | Springer for Research & Development
Endocytosis regulates TDP-43 toxicity and turnover. Nat Commun. 2017;8(1):2092.PubMedPubMedCentralCrossRefGoogle Scholar ... Che M-X, Jiang L-L, Li H-Y, Jiang Y-J, Hu H-Y. TDP-35 sequesters TDP-43 into cytoplasmic inclusions through binding with RNA. ... Dynein and kinesin regulate stress-granule and P-body dynamics. J Cell Sci. 2009;122:3973-82.PubMedPubMedCentralCrossRefGoogle ... TDP-43-mediated neuron loss in vivo requires RNA-binding activity. PLoS One. 2010;5:e12247.PubMedPubMedCentralCrossRefGoogle ...
AggregatesTARDBPFunctions of TDP-43InclusionsDifferentiated motor neuronsAmyotrophicEvidence indicatingProteinsNeuronalMutationsPathogenesisNeuronsFrontotemporal dementiaPathologyProteinopathyHuman TDP-43NeurodegenerationHeterogeneous nuclearBinding-protein 43ProteinopathiesProtein called TDP-43Function of TDP-43BindsFound that TDP-43Show that TDP-43Levels of TDP-43Targets of TDP-43Aggregation of TDP-43PathologicalNeurodegenerative diseasesMutant TDP-43Alzheimer'sCytoplasmCellularDegenerationToxicityGenesEndogenousFindings suggest that TDP-43Highly conservedOverexpressionFamilialMotor neuronAbsence of TDP-43Gene coding forRole for TDP-43Full-length TDP-43AccumulatesTransgenic miceIndicate that TDP-43Localization of TDP-43Abnormally phosphorylatedAbnormal TDP-43MRNA stabilityMiceAutophagyHnRNP
- Neuronal cytoplasmic and intranuclear aggregates of RNA-binding protein TDP-43 are a hallmark feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). (pnas.org)
- Neurons in the affected spinal cord and brain regions showed accumulation of TDP-43 nuclear and cytoplasmic aggregates that were both ubiquitinated and phosphorylated as observed in ALS/FTLD patients. (pnas.org)
- Dominant mutations in two functionally related DNA/RNA-binding proteins, trans-activating response region (TAR) DNA-binding protein with a molecular mass of 43 KDa (TDP-43) and fused in sarcoma/translocation in liposarcoma (FUS/TLS), cause an inherited form of ALS that is accompanied by nuclear and cytoplasmic aggregates containing TDP-43 or FUS/TLS. (pnas.org)
- In 2006, trans-activating response region (TAR) DNA-binding protein with a molecular mass of 43 KDa (TDP-43) was identified as a major component of ubiquinated inclusions found in frontotemporal lobar degeneration with ubiquitin aggregates (FTLD-U) and ALS patients ( 2 , 3 ). (pnas.org)
- TAR DNA-binding protein of 43 kDa (TDP-43) forms pathological aggregates in neurodegenerative diseases, particularly in certain forms of frontotemporal dementia and amyotrophic lateral sclerosis. (medworm.com)
- Changes to the TDP-43 protein cause the protein to misfold and form protein clumps (aggregates), which have been found in nerve cells that control muscle movement (motor neurons) in some people with ALS. (medlineplus.gov)
- It is unclear whether TDP-43 protein aggregates causes the nerve cell death that leads to ALS or if they are a byproduct of a dying cell. (medlineplus.gov)
- TDP-43 is predominantly nuclear, but in cases of neurodegenerative TDP-43 proteinopathies it is present as cytoplasmic aggregates, presumably containing post-translational modifications. (biologists.org)
- Additionally, we show that important proteins involved in neuromuscular junction function, such as syntaxin (SYX), decrease their levels as a consequence of TDP-43 loss of function implying that the degenerative phenotype is a consequence of TDP-43 sequestration into the aggregates. (biologists.org)
- Indeed, protein aggregates are readily found in SOD1-, TDP-43-, FUS- and C9orf72-ALS, the most frequent genetic forms of the disease. (frontiersin.org)
- Consistently, EN6 clears TDP-43 aggregates, a causative agent in frontotemporal dementia, in a lysosome-dependent manner. (nature.com)
- Neurons in patients with dementia or Lou Gehrig's disease often have abnormal aggregates that contain TDP-43* protein, and these accumulated aggregates can cause neurodegeneration by interupting ubiquitin proteasome system (UPS) that removes damaged or unnecessary proteins. (innovations-report.com)
- However, while aggregates of p-TDP-43 were not increased acutely or long-term following TBI, immunoreactivity to phosphorylation-independent TDP-43 was commonly increased in the cytoplasm following TBI with both acute and long-term survival. (springer.com)
- Moreover, zinc could bind to RNA binding domain of TDP-43 and induce the formation of amyloid-like aggregates in vitro. (wikipedia.org)
- The presence of ubiquitinated TDP-43 aggregates and its cleaved TDP-35 and TDP-25 fragments was markedly increased in older, 12-month-old mice leading to larger infarctions and a significant increase in in neuronal death. (biomedcentral.com)
- These results gave us the notion that TFEB is a central regular in trehalose-mediated autophagic clearance of TDP-43 aggregates, representing an important step forward in the treatment of TDP-43 related ALS diseases. (springer.com)
- Concentrate not aggregate - New research explains how the protein TDP43 normally concentrates into droplets and how ALS-related mutations disrupt that, leading to them to form more problematic aggregates that afflict cells. (brown.edu)
- PROVIDENCE, R.I. [Brown University] - In amyotrophic lateral sclerosis, aggregates of the protein TDP-43 are almost always found in afflicted neurons and glial cells. (brown.edu)
- We knew that part of TDP-43 builds up in aggregates and that there are 50 mutations in that domain, but we didn't know the job of that domain, how it goes wrong and why it aggregates," said study corresponding author Nicolas Fawzi, assistant professor in the Department of Molecular Pharmacology, Physiology and Biotechnology at Brown University. (brown.edu)
- Abnormal aggregates of TDP-43 and its hyperphosphorylated and N-terminal truncated C-terminal fragments (CTFs) are deposited as major components of ubiquitinated inclusions in most cases of ALS and FTLD-U. The mechanism underlying the contribution of TDP-43 to the pathogenesis of these neurodegenerative diseases remains unknown. (sigmaaldrich.com)
- About 10 years ago, scientists found aggregates of a protein called TDP-43 in post-mortem neurons from ALS patients. (harvard.edu)
- Since TDP-43 aggregates were discovered in ALS patients, they have been well known as a hallmark of the disease. (harvard.edu)
- In diseased motor neurons where TDP-43 is cleared from the nucleus and forms cytoplasmic aggregates," the authors wrote, "we saw lower protein levels of three genes regulated by TDP-43 and FUS/TLS. (ucsd.edu)
- TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. (jci.org)
- Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp-knockout mice. (jci.org)
- In mice where the TDP-43 gene (Tardbp) was disrupted using a gene trap that carries a beta-galactosidase marker gene, heterozygous (Tardbp(+/-)) mice are fertile and healthy, but intercrosses of Tardbp(+/-) mice yielded no viable homozygotic null (Tardbp(-/-)) mice. (nih.gov)
- Beta-galactosidase staining of tissues from adult Tardbp(+/-) mice shows widespread expression of TDP-43, including prominent levels in various regions of the central nervous system afflicted in neurodegenerative disorders. (nih.gov)
- Although mutations in the gene encoding TDP-43, TARDBP, are found in amyotrophic lateral sclerosis, these are rare. (nih.gov)
- TDP-43 (encoded by TARDBP ) is an ALS-causative gene that we have previously implicated in the regulation of the core stress granule proteins G3BP and TIA-1. (molecularneurodegeneration.com)
- Of the familial cases, ~4% are due to mutations in TARDBP , encoding TAR DNA Binding Protein (TDP-43) [ 2 , 3 ]. (molecularneurodegeneration.com)
- Recently, studies about Tdp-43 protein (Transactive response DNA binding protein 43 kDa, TARDBP), a major common cause of Frontotemporal Dementia (FTD) and so-called Lou Gehrig's Disease (Amyotrophic Lateral Sclerosis, ALS), which spreads muscle paralysis throughout the body have been actively conducted. (eurekalert.org)
- Tat activating regulatory DNA-binding protein (Tardbp or TDP-43), a highly conserved metazoan DNA/RNA binding protein thought to be involved in RNA transcription and splicing, has been linked to the pathophysiology of amyotrophic lateral sclerosis and frontotemporal lobar degeneration and is essential for early embryonic development. (ncku.edu.tw)
- Importantly, high-throughput DNA sequencing analysis on the transcriptome of ES cells lacking Tardbp revealed a set of downstream targets of TDP-43. (ncku.edu.tw)
- Missense mutations in the TDP-43 gene ( TARDBP ), mostly in the C-terminal glycine-rich region, have been identified in patients with ALS ( 10 , 11 ), and ALS associated with FTLD ( 12 ). (pnas.org)
- However, in FTLD and in the majority of familial and sporadic ALS patients, no TARDBP mutations are identified, suggesting that wild-type (WT) TDP-43 is central to the disease cascade ( 9 , 13 ). (pnas.org)
- To identify neurons specifically vulnerable to increased TDP-43 levels, we generated germline transgenic mouse lines overexpressing human TARDBP (TDP43 WT ). (pnas.org)
- We generated several germline transgenic mouse lines overexpressing human wild-type TARDBP (TDP43 WT ) under the control of a neuronal murine Thy-1 (mThy-1) promoter that drives transgene expression in virtually all neurons of the central nervous system ( Fig. 1 A ) and becomes active approximately 1 week after birth ( 16 ). (pnas.org)
- Western Blot: TDP-43/TARDBP Antibody (2E2-D3) [H00023435-M- TARDBP monoclonal antibody (M01), clone 2E2-D3 Analysis of TARDBP expression in A-431. (novusbio.com)
- Immunocytochemistry/ Immunofluorescence: TDP-43/TARDBP Antibody (2E2-D3) [H00023435-M- Analysis of monoclonal antibody to TARDBP on HeLa cell. (novusbio.com)
- Immunohistochemistry-Paraffin: TDP-43/TARDBP Antibody (2E2-D3) [H00023435-M- Analysis of monoclonal antibody to TARDBP on formalin-fixed paraffin-embedded human leiomyosarcoma tissue Antibody concentration 3 ug/ml. (novusbio.com)
- Immunohistochemistry-Paraffin: TDP-43/TARDBP Antibody (2E2-D3) [H00023435-M- TARDBP in rat tissue samples. (novusbio.com)
- Immunohistochemistry-Paraffin: TDP-43/TARDBP Antibody (2E2-D3) [H00023435-M- TARDBP on formalin-fixed paraffin-embedded human leiomyosarcoma. (novusbio.com)
- ELISA: TDP-43/TARDBP Antibody (2E2-D3) [H00023435-M- Detection limit for recombinant GST tagged TARDBP is 0.3 ng/ml as a capture antibody. (novusbio.com)
- Transactivation response element DNA-binding protein 43 (TDP-43, TARDBP ), is a heterogeneous nuclear ribonucleoprotein (hnRNP) thought to provide the neuropathological link to establish such a disease spectrum ( 1 , 3 ). (sciencemag.org)
- The TARDBP gene provides instructions for making a protein called transactive response DNA binding protein 43 kDa (TDP-43). (medlineplus.gov)
- Most TARDBP gene mutations that cause FTD change single amino acids in the TDP-43 protein. (medlineplus.gov)
- TDP-43 (also known as TARDBP) regulates different processes of gene expression, including transcription and splicing, through RNA and DNA binding. (biologists.org)
- The TAR DNA-binding protein (TARDBP, hereafter referred to as TDP-43) is a highly conserved heterogeneous nuclear ribonucleoprotein (hnRNP) ( Krecic and Swanson, 1999 ) that controls the transcription, splicing and RNA stability of specific genes (for a review, see Buratti and Baralle, 2008 ). (biologists.org)
- Transactive response DNA-binding protein 43 kDa (TDP-43, also known as TBPH in Drosophila melanogaster and TARDBP in mammals) is the main protein component of the pathological inclusions observed in neurons of patients affected by different neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). (biologists.org)
- TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa), is a protein that in humans is encoded by the TARDBP gene. (wikipedia.org)
- Humans carry an RNA-processing protein called the transactive response DNA-binding protein, or TARDBP/TDP-43. (asbmb.org)
- TDP-43 (Tat activating regulatory DNA-binding protein, TARDBP) has been linked to the pathophysiology of ALS and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). The TDP-43 gene encodes a highly conserved DNA/RNA binding protein thought to be involved in RNA transcription and splicing. (sigmaaldrich.com)
Functions of TDP-437
- Whereas a pathological link to neurodegenerative disorders has been established, the cellular and physiological functions of TDP-43 remain unknown. (nih.gov)
- The normal functions of TDP-43 are not established, although it has been proposed that TDP-43 is involved in transcription repression ( 12 , 13 ) and splicing regulation ( 14 - 16 ). (pnas.org)
- A detailed description of the determinants for cellular localization has yet to emerge, including information on how the known functions of TDP-43 and cellular targeting affect each other. (biologists.org)
- And, what are the really important functions of TDP-43 that happen in cells, functions that would cause the degeneration of neurons without them? (slu.edu)
- Interestingly, it was determined that the glutamate transporter EAAT1 mediates the regulatory functions of TDP-43 in the glia, and genetic or pharmacological compensations of EAAT1 activity were demonstrated to be sufficient to modulate glutamate receptor clustering and locomotive behaviors in flies. (sdbonline.org)
- The data uncovers autonomous and non-autonomous functions of TDP-43 in glia and suggests new experimentally based therapeutic strategies in ALS. (sdbonline.org)
- But, he cautions, first "we need to learn more about normal functions of TDP-43. (asbmb.org)
- In amyotrophic lateral sclerosis, TDP-43 is mislocalized from the nucleus to the cytoplasm of diseased motor neurons, forming ubiquitinated inclusions. (nih.gov)
- Since then, intracellular TDP-43-positive inclusions have been found in an array of neurodegenerative diseases, including Alzheimer's disease (AD), Pick's disease, various forms of Parkinson's diseases (PD), and others ( 4 ). (pnas.org)
- This evidence has shaped an emerging TDP-43 proteinopathy hypothesis in which sequestration of nuclear TDP-43 into pathological inclusions is proposed to contribute to disease pathogenesis ( 8 ). (pnas.org)
- The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. (medworm.com)
- Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a major protein component within ubiquitin-positive inclusions of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. (mcponline.org)
- Although TDP-43 is a nuclear DNA/RNA-binding protein, in pathological conditions, TDP-43 has been reported to redistribute to the cytoplasm where it is cleaved and forms insoluble, ubiquitinated, and phosphorylated inclusions. (mcponline.org)
- Whereas recombinant and endogenous TDP-43 was primarily localized in the nucleus, the shorter TDP-S6 formed highly insoluble cytoplasmic and nuclear inclusions reminiscent of disease-specific pathology. (mcponline.org)
- Immunofluorescence showed strong co-localization of endogenous Ub with both cytoplasmic and nuclear TDP-S6 inclusions, whereas SUMO-2/3 was co-localized mainly with the nuclear inclusions. (mcponline.org)
- In addition to the aggregation of tau in some forms of FTLD, more than half of cases are marked by ubiquitin-positive inclusions and are subclassified as FTLD-U. Transactive response (TAR) DNA-binding protein 43 (TDP-43) has been identified as a major protein component of inclusions in FTLD-U and amyotrophic lateral sclerosis (ALS) ( 5 ). (mcponline.org)
- Although physiological TDP-43 resides mainly in the nucleus, pathology-relevant TDP-43 redistributes from the nucleus to the cytoplasm where it is cleaved and forms phosphorylated and ubiquitinated inclusions ( 5 , 17 - 19 ). (mcponline.org)
- In sporadic ALS (~97% of all cases) and sporadic FTD (~45% of all cases), TDP-43 clears from the nucleus and forms ubiquitinated, cytoplasmic inclusions, termed TDP-43 proteinopathy ( 2 ). (sciencemag.org)
- TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. (broadinstitute.org)
- Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease. (wikipedia.org)
- TDP43-positive intraneuronal inclusions in a patient with motor neuron disease and Parkinson's disease. (wikipedia.org)
- Colocalization of transactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington disease. (wikipedia.org)
- Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado-Joseph disease. (wikipedia.org)
- The pathologic phosphorylation and sub-cellular translocation of neuronal transactive response-DNA binding protein (TDP-43) was identified as the major disease protein in frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions, now termed FTLD-TDP, and amyotrophic lateral sclerosis (ALS). (springer.com)
- No association was found between a history of single TBI and abnormally phosphorylated TDP-43 (p-TDP-43) inclusions. (springer.com)
- Normally expressed in nucleus, under pathological conditions TDP-43 forms cytoplasmic ubiquitinated inclusions in which it is abnormally phosphorylated and cleaved to generate a 35 and a 25 kDa C-terminal fragments. (biomedcentral.com)
- We report here an age-related increase and formation of ubiquitinated TDP-43 cytoplasmic inclusions after stroke. (biomedcentral.com)
- Importantly, unlike the hallmark neuropathological features associated with chronic neurodegenerative disorders, the TDP-43-positive cytoplasmic inclusions detected after stroke were not phosphorylated. (biomedcentral.com)
- Non-amyloid, ubiquitinated cytoplasmic inclusions containing TDP-43 and its C-terminal fragments are pathological hallmarks of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Importantly, TDP-43 mutations are linked to sporadic and non-SOD1 familial ALS. (semanticscholar.org)
- Transactive response DNA-binding protein 43 kDa (TDP-43) was identified as a major disease-associated component in the brain of patients with amyotrophic lateral sclerosis (ALS), as well as the largest subset of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), which characteristically exhibits cytoplasmic inclusions that are positive for ubiquitin but negative for tau and α-synuclein. (springer.com)
- The 25-kDa C-terminal fragment (CTF) of caspase-cleaved TDP-43 leads to the formation of toxic cytoplasmic inclusions within cells. (sigmaaldrich.com)
- A nuclear protein, TDP-43, accumulates in the cytoplasmic inclusions in the sporadic ALS lesions with post-transcriptional modifications, such as ubuiquitination, phosphorylation and truncation, and it works as a pathologic protein of the disease. (nii.ac.jp)
- Amyotrophic lateral sclerosis is a neurodegenerative disease characterized clinically by motor symptoms including limb weakness, dysarthria, dysphagia, and respiratory compromise, and pathologically by inclusions of transactive response DNA-binding protein 43 kDa (TDP-43). (biomedcentral.com)
- FTLD cases that are characterized by TDP-43 inclusions can be passed from one generation to the next, as a result of mutations in another protein called progranulin (GRN). (medicalxpress.com)
Differentiated motor neurons1
- MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis. (nih.gov)
- However, TDP-43 pathology is common to over 95% of amyotrophic lateral sclerosis cases, suggesting that abnormalities of TDP-43 play an active role in disease pathogenesis. (nih.gov)
- It is our hypothesis that a loss of TDP-43 from the nucleus of affected motor neurons in amyotrophic lateral sclerosis will lead to changes in RNA processing and expression. (nih.gov)
- four were validated by immunofluorescence labelling of motor neurons in TDP-43(A315T) mice, and two of these were confirmed by immunohistochemistry in amyotrophic lateral sclerosis cases. (nih.gov)
- This discovery-based approach has for the first time revealed translational changes in motor neurons of a TDP-43 mouse model, identifying DDX58 and MTHFSD as two TDP-43 targets that are misregulated in amyotrophic lateral sclerosis. (nih.gov)
- TDP-43 is linked to pathogenesis of major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). (prolekarniky.cz)
- TAR-DNA binding protein (TDP-43) is an RNA-binding protein that has been suggested to play a major role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) - . (prolekarniky.cz)
- Cytoplasmic aggregation of TDP-43, accompanied by its nuclear clearance, is a key common pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). (sciencemag.org)
- Loss of nuclear TDP-43 in amyotrophic lateral sclerosis (ALS) causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurones. (medlineplus.gov)
- The aberrant cellular distribution and aggregation of TDP-43 were recently reported in neurodegenerative diseases, namely frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). (biologists.org)
- Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. (wikipedia.org)
- Mackenzie IRA, Rademakers R, Neumann M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. (springer.com)
- Autophagy regulates amyotrophic lateral sclerosis-linked fused in sarcoma-positive stress granules in neurons. (springer.com)
- Alterations in the glial function of TDP-43 are becoming increasingly associated with the neurological symptoms observed in Amyotrophic Lateral Sclerosis (ALS), however, the physiological role of this protein in the glia or the mechanisms that may lead to neurodegeneration are unknown. (sdbonline.org)
- The RNA-processing protein TDP-43 is central to the pathogenesis of amyotrophic lateral sclerosis (ALS) , the most common adult-onset motor neuron (MN) disease. (sdbonline.org)
- A hyper-phosphorylated, ubiquitinated and cleaved form of TDP-43-known as pathologic TDP43-is the major disease protein in ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal dementia (FTLD-TDP, previously referred to as FTLD-U) and in Amyotrophic lateral sclerosis (ALS). (wikipedia.org)
- TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. (semanticscholar.org)
- The relevance of contact-independent cell-to-cell transfer of TDP-43 and SOD1 in amyotrophic lateral sclerosis. (semanticscholar.org)
- TDP-43 is a protein which is strongly linked to Amyotrophic Lateral Sclerosis (ALS, a form of motor neuron disease) and Fronto-Temporal Dementia (FTD, the second most common form of dementia), but exactly how the protein causes neurodegeneration is not properly understood. (kcl.ac.uk)
- Scyl1 and Scyl3 double-deficient mice had neuronal defects characteristic of amyotrophic lateral sclerosis, including TDP-43 pathology, at an earlier age than did Scyl1 -deficient mice. (jneurosci.org)
- TDP-43 levels are higher in platelets from patients with sporadic amyotrophic lateral sclerosis than in healthy controls. (ptglab.com)
- PHILADELPHIA - Lou Gehrig's disease, or amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration (FTLD) are characterized by protein clumps in brain and spinal-cord cells that include an RNA-binding protein called TDP-43. (scienceblog.com)
- DESCRIPTION (provided by applicant): The TDP-43 protein plays a role in a broad suite of neurodegenerative disorders including Frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis, and potentially Alzheimer's disease. (neurodegenerationresearch.eu)
- We suggest that these findings are likely relevant to the pathogenic mechanism of a broad array of TDP-43 proteinopathies, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis. (uzh.ch)
- Both of these identified genes, DDX58 and MTHFSD, are RNA-binding proteins, and we show that TDP-43 binds to their respective mRNAs and we identify MTHFSD as a novel component of stress granules. (nih.gov)
- Under conditions of stress, TDP-43 translocates from the nucleus to the cytoplasm, competes with FOXO transcription factors for binding to 14-3-3 proteins, and releases FOXO for nuclear translocation and activation. (prolekarniky.cz)
- Tdp-43 is a protein that regulates the process of making proteins from genes. (eurekalert.org)
- Using isogenic cell lines expressing wild-type or ALS-linked TDP-43 mutants and fibroblasts from a human patient, pulse-chase radiolabeling of newly synthesized proteins is used to determine, surprisingly, that ALS-linked TDP-43 mutant polypeptides are more stable than wild-type TDP-43. (pnas.org)
- Tandem-affinity purification and quantitative mass spectrometry are used to identify TDP-43 complexes not only with heterogeneous nuclear ribonucleoproteins family proteins, as expected, but also with components of Drosha microprocessor complexes, consistent with roles for TDP-43 in both mRNA processing and microRNA biogenesis. (pnas.org)
- In addition to a nuclear function, TDP-43 also colocalizes with fragile X mental-retardation protein (FMRP) and Staufen proteins in the neurites of primary neurons, which suggests a role in RNA transport and localization ( 20 ). (pnas.org)
- When TDP-43 was depleted in cells, a set of nonconserved cryptic exons spliced into target RNAs, leading to down-regulation of corresponding proteins critical for cellular function. (sciencemag.org)
- The TDP-43 protein attaches (binds) to DNA and regulates an activity called transcription, which is the first step in the production of proteins from genes. (medlineplus.gov)
- The TDP-43 protein is involved in processing molecules called messenger RNA (mRNA), which serve as the genetic blueprints for making proteins. (medlineplus.gov)
- By cutting and rearranging mRNA molecules in different ways, the TDP-43 protein controls the production of different versions of certain proteins. (medlineplus.gov)
- Many of the proteins whose production is influenced by the TDP-43 protein are involved in nervous system and organ development. (medlineplus.gov)
- For TDP-43 and other RNA binding proteins, very little is known about when they will form, how many will form and how big they are. (slu.edu)
- The SLU team decided to see if phosphorylation - one of the most common ways that proteins are regulated - may be responsible for managing the activity, location and how tightly the protein binds. (slu.edu)
- The research team found a new role of three proteins (PTK2, TBK1, SQSTM1) which can inhibit neuronal degeneration by TDP-43 and demonstrated for the first time that their interaction can alleviate neurodegeneration by strengthening "autophagy lysosome pathway (ALP),*" which consists of another protein quality control system in case of damage to the UPS. (innovations-report.com)
- In a search for proteins that may affect microglia/neuron immune crosstalk in aging brain, we focused our study on transactive response (TAR) DNA binding protein 43 (TDP-43). (biomedcentral.com)
- Unlike people who have Alzheimer's disease, people with limbic-predominant age-related TDP-43 encephalopathy (LATE) don't accumulate beta-amyloid or tau proteins in their brains. (newscientist.com)
- Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. (rupress.org)
- TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. (rupress.org)
- Stress granule recruitment and deposition of proteins of the FET family and TDP-43 in ALS and FTD. (uni-muenchen.de)
- TDP-43 pathology occurs in distinct brain regions, involves disparate brain networks, and features accumulation of misfolded proteins in various cell types and in different neuroanatomical regions. (springer.com)
- Together, our results demonstrate an overlapping role for SCYL1 and SCYL3 in vivo and highlight the importance the SCYL family of proteins in regulating neuronal function and survival. (jneurosci.org)
- Background: TAZ is a transcriptional co-activator with a PDZ-binding motif that is regulated by its interaction with 14-3-3 proteins (1). (cellsignal.com)
- In general, TDP-43 acts like a chaperone for RNA in a cell, binding to it, guiding its processing, transporting it to where it needs to go and regulating it, so that other proteins can be expressed properly. (brown.edu)
- Further explain that in 10 pro athletes with a history of repeated head trauma, pathologists discovered extensive brain deposits of a DNA-binding protein called TDP-43 and neurofibrillary tau protein -- but the tau proteins found in three motor neuron disease cases were different from those seen in sporadic ALS patients. (medpagetoday.com)
- The deposits of the TDP-43 and tau proteins, found post-mortem in numerous regions of 10 of the pro athletes' brains provided "the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease," the researchers commented. (medpagetoday.com)
- Additionally we are shipping Granulin Kits (120) and Granulin Proteins (43) and many more products for this protein. (antibodies-online.com)
- TDP-43 is one of many proteins that binds to RNA, which is responsible for transmitting genetic information and translating it into a concise recipe for a given protein, for example, part of a growing neuron. (harvard.edu)
- The two proteins that contribute to the disease - FUS/TLS and TDP-43 - bind to ribonucleic acid (RNA), intermediate molecules that translate genetic information from DNA to proteins. (ucsd.edu)
- TDP-43 is a known protein widely expressed throughout the body, with multiple functions, including regulating transcription of the genetic code and as scaffolding for nuclear and motor neuron proteins. (medicalxpress.com)
- The identification of misfolded TDP-43 proteins in neurons of brain tissue (brown structures indicated by arrows) was a criterion for entry into this genome-wide study. (medicalxpress.com)
- How TDP-43, GRN, and TMEM106B proteins might normally interact in brain cells and be disrupted in FTLD remains to be deciphered. (medicalxpress.com)
- These data raise the possibility that disruptions of normal stress granule dynamics by loss of nuclear TDP-43 function may contribute to neuronal vulnerability in ALS. (molecularneurodegeneration.com)
- Indeed, Tdp-43 is a tightly autoregulated ( 10 ), essential gene ( 11 - 13 ) that is required for neuronal physiology in mice ( 14 ), fruit flies ( 15 ), and zebrafish ( 16 ). (sciencemag.org)
- Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. (broadinstitute.org)
- Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. (nature.com)
- It has also shown to be a neuronal activity response factor in the dendrites of hippocampal neurons suggesting possible roles in regulating mRNA stability, transport and local translation in neurons. (wikipedia.org)
- Together, our findings suggest that the level of cytoplasmic TDP-43 increases with aging and may act as an age-related mediator of inflammation and neuronal injury after stroke. (biomedcentral.com)
- Here, we aim to summarize recent advances in the neuropathology, genetics and animal models of TDP-43 proteinopathy, and their relationship to clinical phenotypes for the underlying selective neuronal and regional susceptibilities. (springer.com)
- As TDP-43 misaggregation is noted in ALS patients' cells, these new findings give researchers new targets to consider while attempting to understand neuronal loss in ALS and similar neurodegenerative disorders. (neurosciencenews.com)
- It is possible that the loss of TDP-43 may lead not only to the neuronal loss seen in ALS patients, but also neuronal loss in other neurodegenerative disorders. (neurosciencenews.com)
- Studies have pointed to a role for SCYL1 and SCYL2 in regulating neuronal function and viability in mice and humans, but little is known about the biological function of SCYL3. (jneurosci.org)
- In the 2016 article, the authors wrote that they found that TDP-43 accumulated in neuronal mitochondria in subjects with ALS or frontotemporal dementia. (padiracinnovation.org)
- demonstrate that one of the two mitochondrial TDP-43 inhibitory peptides of the 2016 article, when administered late in the course of the disease, may attenuate the development and progression of cerebral neuronal loss and behavioral deficits in the 5XFAD transgenic mouse model in Alzheimer's disease. (padiracinnovation.org)
- PM1 abolished TDP-43 protein kinetics, reversed neuronal loss, and reduced neuroinflammation in aged 5XFAD mice long after symptom onset. (padiracinnovation.org)
- Chronic administration of the PM1 peptide significantly attenuated TDP-43 protein kinetics, mitochondrial abnormalities, microgliosis, and even neuronal loss, but was without effect on amyloid plaque load in 12-month-old 5XFAD mice well after the onset of symptoms. (padiracinnovation.org)
- For example, accumulating abnormal TDP-43 and FUS/TLS in neuronal cytoplasm has been documented in frontotemporal lobar dementia, a neurological disorder that has been shown to be genetically and clinically linked to ALS, and which is the second most frequent cause of dementia after Alzheimer's disease. (ucsd.edu)
- Interestingly, a proportion of sporadic ALS cases have also been attributed to TDP-43 mutations [ 2 , 3 ]. (molecularneurodegeneration.com)
- Though missense mutations in TDP-43 cause rare forms of familial ALS, it is not yet known whether this is due to loss of TDP-43 function or gain of aberrant function. (pnas.org)
- Starting in 2008, multiple studies identified over 30 dominant mutations in TDP-43 in both sporadic and familial ALS patients but not in other neurodegenerative diseases including AD or PD, indicating that these mutations are specific to ALS pathogenesis ( 4 - 7 ). (pnas.org)
- However, how ALS-linked mutations in TDP-43 and FUS/TLS contribute to cellular toxicity is not understood. (pnas.org)
- Whether nuclear or cytoplasmic, the RNA targets and protein interactors of TDP-43 have not yet been systematically identified, and it is not known how ALS-linked mutations in TDP-43 affect its normal function(s). (pnas.org)
- Missense mutations in TDP-43 are also linked to familial ALS, strongly supporting the idea that TDP-43 proteinopathy is central to the pathogenesis of sporadic disease ( 4 , 5 ). (sciencemag.org)
- Numerous genetic mutations associated with familial ALS-FTD- VCP , GRN , OPTN , ATXN2 , SQSTM1 , UBQLN2 , PFN1 , TBK1 , and especially C9ORF72 -result in TDP-43 proteinopathy, suggesting a convergent mechanism of neurodegeneration ( 6 - 9 ). (sciencemag.org)
- Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. (broadinstitute.org)
- The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. (broadinstitute.org)
- TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. (broadinstitute.org)
- Thus, TDP-43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43. (broadinstitute.org)
- Most mutations change single protein building blocks (amino acids) in the TDP-43 protein. (medlineplus.gov)
- TDP-43 is conserved in Drosophila, where it has been the topic of considerable study, but how TDP-43 mutations lead to age-dependent neurodegeneration is unclear and most approaches have not directly examined changes in MN morphology with age. (sdbonline.org)
- Expression of the mutant protein TDP-43(Q331K) caused dying-back of NMJs and axons, which could not be suppressed by mutations that block Wallerian degeneration. (sdbonline.org)
- Meanwhile, about 50 ALS-linked mutations are known to affect a particular region of TDP-43. (brown.edu)
- Missense mutations in TDP-43 have been found in autosomal dominant ALS families, suggesting that mutant TDP-43 may be a primary cause of motor neuron degeneration. (sigmaaldrich.com)
- Mutations in the gene for TDP-43 are responsible for some cases of familial ALS, but some 90% of ALS cases are sporadic with no known genetic cause. (medpagetoday.com)
- Here we demonstrate that VCP and TDP-43 interact genetically and that disease-causing mutations in VCP lead to redistribution of TDP-43 to the cytoplasm in vitro and in vivo, replicating the major pathology observed in IBMPFD and other TDP-43 proteinopathies. (uzh.ch)
- Together, our results show that degeneration associated with VCP mutations is mediated in part by toxic gain of function of TDP-43 in the cytoplasm. (uzh.ch)
- From this, the team concluded that the TMEM106B gene variants confer a higher genetic risk for all FTLD-TDP patients, as well as in the subset of patients with GRN mutations. (medicalxpress.com)
- Our data lend further support to the role of TDP-43 loss-of-function in the pathogenesis of neurodegenerative disorders. (biologists.org)
- Hyung-Jun Kim, the principal researcher at KBRI and senior author of the study, said, "this research reveals the pathogenesis of TDP-43 associated neurodegeneration at the basic level, so further clinical verification process is necessary to develop a therapy for dementia. (innovations-report.com)
- Chang CF, Lee YC, Lee KH, Lin HC, Chen CL, Shen CJ, Huang CC (2016) Therapeutic effect of berberine on TDP-43-related pathogenesis in FTLD and ALS. (springer.com)
- Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis. (rupress.org)
- Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons, but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS. (jci.org)
- Here we have used translating ribosome affinity purification coupled with microarray analysis to identify the mRNAs being actively translated in motor neurons of mutant TDP-43(A315T) mice compared to age-matched non-transgenic littermates. (nih.gov)
- The collaborative research team confirmed that different kinds of cryptic exons were produced depending on the cell types such as muscle cells and neurons after an experiment using gene-manipulated mice that were prevented from expressing Tdp-43 protein in the desired cells. (eurekalert.org)
- Generating homozygous and hemizygous WT human TDP-43 transgenic mouse lines, we show here a dose-dependent degeneration of cortical and spinal motor neurons and development of spastic quadriplegia reminiscent of ALS. (pnas.org)
- These findings suggest that ≈25-kDa TDP-43 CTFs are noxious to neurons by a gain of aberrant nuclear function. (pnas.org)
- We show here that overexpression of WT TDP-43 leads to degeneration of specific neurons in the central nervous system, including spinal and cortical motor neurons and nonmotor cortical neurons characteristically affected in FTLD-TDP, and causes spastic quadriplegia in a dose-dependent manner. (pnas.org)
- Here we present a cellular model in which full-length human TDP-43 or a splicing isoform (TDP-S6) that lacks the C terminus is overexpressed in a human cell line and mouse primary neurons. (mcponline.org)
- This research is regarded as one that presents new therapeutic strategies that can remove abnormal protein accumulation in the neurons of patients with dementia in the future by revealing a new molecular mechanism that restores neurodegeneration by TDP-43 protein, which has been the major cause of dementia and Lou Gehrig diseases. (innovations-report.com)
- Recent work has characterized the transcriptome-wide binding sites revealing that thousands of RNAs are bound by TDP-43 in neurons. (wikipedia.org)
- In spinal motor neurons TDP-43 has also been shown in humans to be a low molecular weight neurofilament (hNFL) mRNA-binding protein. (wikipedia.org)
- In the present study, we investigated age-related expression patterns of TDP-43 in neurons and glia and its role as modulator of inflammation following ischemic injury. (biomedcentral.com)
- Depletion of a protein called TDP-43 has been previously linked to the death of motor neurons, leading to ALS. (eurekalert.org)
- We demonstrated that U6 snRNA, regulated by TDP-43, plays an important role in maintaining motor neurons but its mechanism is still shrouded in mystery. (eurekalert.org)
- Disease onset also correlated with the mislocalization of TDP-43 in spinal motor neurons, suggesting that SCYL1 and SCYL3 regulate TDP-43 proteostasis. (jneurosci.org)
- Clearly, some of the genes at work in the trash-disposal system of neurons, known as the proteasome, were interacting with TDP-43 in a way that precipitated ALS. (harvard.edu)
- The researchers set out to identify, for the first time, all the possible types of RNA regulated by the TDP-43 protein in the context of human neurons. (harvard.edu)
- The researchers reduced the levels of TDP-43 protein in human stem cell-derived motor neurons. (harvard.edu)
- In a study published in the Journal of Clinical Investigation , a team led by Virginia M.-Y. Lee, PhD, director of Penn's Center for Neurodegenerative Disease Research, describes the first direct evidence of how mutated TDP-43 can cause neurons to die. (scienceblog.com)
- In the case of TDP-43, neurons could die for two reasons: One, the clumps themselves are toxic to neurons or, two, when TDP-43 is bound up in clumps outside the nucleus, it depletes the cell of normally functioning TDP-43. (scienceblog.com)
- To determine the effects of misplaced TDP-43 on the viability of neurons, the researchers made transgenic mice expressing human mutated TDP-43 in the cytoplasm and compared them to mice expressing normal human TDP-43 in the nucleus of nerve cells. (scienceblog.com)
- Neurodegeneration in the mouse neurons expressing TDP-43 - both the normal and mutated human versions - was accompanied by a dramatic downregulation of the TDP-43 protein mice are born with. (scienceblog.com)
- What's more, mice expressing the mutated human TDP-43 exhibited profound changes in gene expression in neurons of the brain's cortex. (scienceblog.com)
- The findings suggest that disturbing the normal TDP-43 in the cell nucleus results in loss of normal TDP-43 function and gene regulatory pathways, culminating in degeneration of affected neurons. (scienceblog.com)
- So our discovery provides a plausible hypothesis for toxic effects of TDP-43 in neurons. (neurodegenerationresearch.eu)
- Scientists expect to elucidate pathogenic mechanisms of Frontotemporal Dementia (FTD) and other diseases once they find how Tdp-43 protein and cryptic exons* interact with each other depending on the cellular context. (eurekalert.org)
- TDP-43 aggregation is also observed in hereditary inclusion body myopathy and Paget disease of the bone with frontotemporal dementia ( 6 ) as well as in some cases of Alzheimer and Parkinson diseases ( 7 , 8 ). (mcponline.org)
- In 2006, researchers discovered that TDP-43 was the main feature of neurological disorders like ALS and frontotemporal dementia. (slu.edu)
- In addition to ALS, TDP-43 is found in cases of frontotemporal dementia, a type of dementia that is distinct from Alzheimer's disease. (slu.edu)
- And, scientists know that in ALS and frontotemporal dementia, the aggregating protein is TDP-43. (slu.edu)
- But in 97 per cent of people with ALS and nearly half of the people with frontotemporal dementia, TDP-43 is found outside the cell nucleus in an area called the cytoplasm. (als.ca)
- An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). (medworm.com)
- Together our data indicate that expression of a TDP-43 splice variant lacking a C terminus recapitulates many of the cellular and biochemical features associated with disease pathology and that the interplay of ubiquitination and SUMOylation may have an important role in TDP-43 regulation. (mcponline.org)
- Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. (springer.com)
- While the connection to Alzheimer's is not yet understood, scientists speculate that TDP-43 may be a secondary pathology or a marker of Alzheimer's disease. (slu.edu)
- Specifically, just 3 of 62 TBI cases displayed p-TDP-43 pathology versus 2 of 47 control cases. (springer.com)
- Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy. (wikipedia.org)
- The clinical phenotypes of ALS and FTLD-TDP (FTLD with abnormal intracellular accumulations of TDP-43) correlate with characteristic distribution patterns of the underlying pathology across specific brain regions with disease progression. (springer.com)
- No signs of TDP-43 or other pathology like that of the athletes were seen in any of the normal controls. (medpagetoday.com)
- The molecular mechanisms by which TDP-43 contributes to the pathology of ALS remained elusive. (padiracinnovation.org)
- Since the amyloid plaque load was not attenuated or prevented by PM1, the authors' results clearly indicate that TDP-43 in mitochondria does not affect the pathology of Aβ. (padiracinnovation.org)
- TDP-43 pathology was present in 11 patients (33.3%), including components in both basal forebrain (n= 10) and hypothalamus (n= 7). (biomedcentral.com)
- This pathology was associated with non-motor system TDP-43 pathology (Χ 2 = 17.5, p= 0.00003) and bulbar symptoms at onset (Χ 2 = 4.04, p= 0.044), but not age or disease duration. (biomedcentral.com)
- Furthermore, TDP-43 pathology in the lateral hypothalamic area was associated with reduced body mass index (W= 11, p= 0.023). (biomedcentral.com)
- Senior Researcher Yun Ha Jeong from the Korea Brain Research Institute said, "This study suggests that Tdp-43 proteinopathy and specific cryptic exons are involved in the process of degenerative brain and muscle disorders in a unique way. (eurekalert.org)
- show that the main culprit of proteinopathy, TDP-43, acts as a splicing suppressor of nonconserved cryptic exons. (sciencemag.org)
- Because brains of ALS-FTD cases showed evidence of missplicing of cryptic exons, failure in these regions may underlie TDP-43 proteinopathy. (sciencemag.org)
- However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. (sciencemag.org)
- Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy. (sciencemag.org)
- More recently, TDP-43 proteinopathy has been reported in dementia pugilistica or chronic traumatic encephalopathy caused by repetitive traumatic brain injury (TBI). (springer.com)
- While a single TBI has been linked to the development of Alzheimer's disease and an increased frequency of neurofibrillary tangles, TDP-43 proteinopathy has not been examined with survival following a single TBI. (springer.com)
- Moreover, while single TBI can induce multiple long-term neurodegenerative changes, the absence of TDP-43 proteinopathy may indicate a fundamental difference in the processes induced following single TBI from those of repetitive TBI. (springer.com)
- Finally, we attempt to integrate these findings into the emerging picture of TDP-43 proteinopathy, and to highlight key issues for future therapy and research. (springer.com)
- In this review, we summarize recent advances in the neuropathology, genetics and animal models of TDP-43 proteinopathy, and discuss their relationship to clinical phenotypes, their place in the emerging picture of TDP-43 proteinopathy, and their relevance to the development of therapeutic interventions. (springer.com)
- Tdp-43 Cryptic Exons are Highly Variable between Cell Types," Molecular Neurodegeneration 2017. (eurekalert.org)
- Three genes were identified that suppress TDP-43 toxicity, including shaggy /GSK3 , a known modifier of neurodegeneration. (sdbonline.org)
- Linking neurodegeneration to vascular dysfunction - Loss of ALS/FTD-associated TDP-43 causes angiogenic defects. (uni-muenchen.de)
- The long noncoding RNA neuroLNC regulates presynaptic activity by interacting with the neurodegeneration-associated protein TDP-43. (mpg.de)
- Also, studies in animal models suggest that overexpression of TDP-43 leads to neurodegeneration, and the protein has also been found in humans with a variety of such diseases including Alzheimer's disease, Lewy body disease, and Pick disease. (medpagetoday.com)
- So while the importance of TDP-43 in neurodegeneration is established, the mechanisms of TDP-43 toxicity are unclear. (neurodegenerationresearch.eu)
- Bearing features of a heterogeneous nuclear ribonucleoprotein (hnRNP), TDP-43 has well-characterized RNA-processing functions - . (prolekarniky.cz)
- TDP-43 is a heterogeneous nuclear ribonucleoprotein (hnRNP) and is reported to function in multiple aspects of RNA metabolism including transcription, splicing, and stabilization [ 4 ]. (molecularneurodegeneration.com)
- TDP-43 interacts with heterogeneous nuclear ribonucleoproteins (hnRNP) A2/B1 and hnRNP C in vitro, and these interactions may be required for splicing site selection ( 19 ). (pnas.org)
- TDP-43 is a heterogeneous nuclear ribonucleoprotein with two RNA recognition motifs (RRM-1 and 2) in the middle portion [ 93 ] and a glycine-rich domain and glutamine/asparagine (Q/N)-rich domain in the C-terminal region. (springer.com)
- Tar DNA-binding protein 43 (TDP-43) is an RNA-binding protein normally localized to the nucleus of cells, where it elicits functions related to RNA metabolism such as transcriptional regulation and alternative splicing. (nih.gov)
- The recent identification of the TAR DNA-binding protein-43 (TDP-43) as a major protein constituent of NCIs and NIIs in ALS and FTLD (FTLD-U or FTLD-TDP) patients has offered a molecular link between these two disorders ( 4 , 5 ). (pnas.org)
- Lin, W.L., M. Castanedes-Casey, and D.W. Dickson, Transactivation response DNA-binding protein 43 microvasculopathy in frontotemporal degeneration and familial Lewy body disease. (wikipedia.org)
- Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. (springer.com)
- TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. (springer.com)
- The mechanism for trehalose-induced autophagy enhancement is not clear, and its therapeutic effect on TAR DNA-binding protein-43 (TDP-43) proteinopathies has been poorly investigated. (springer.com)
- one of these was TBPH, the Drosophila homolog of TAR (trans-activating response region) DNA-binding protein 43 (TDP-43). (uzh.ch)
- This indicates that a common underlying mechanism may broadly define a spectrum of neurodegenerative disorders termed "TDP-43 proteinopathies" ( 9 , 10 ). (mcponline.org)
- If this peptide is effective against TDP-43 proteinopathies, it is a real breakthrough because a peptide is something that is easy to produce at a low cost. (padiracinnovation.org)
Protein called TDP-433
- But previous studies have implicated a misshapen form of a different protein, called TDP-43 , in the condition. (newscientist.com)
- A protein called TDP-43 is usually found inside the cell nucleus where it plays an essential role in regulating many cellular processes. (als.ca)
- They led an international team that found that a protein called TDP-43 accumulates abnormally in brain tissue from individuals with one type of heritable FTLD. (medicalxpress.com)
Function of TDP-432
- Ayala and her lab study TDP-43, a protein that binds to RNA and plays a role in gene expression. (slu.edu)
- TDP-43 is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. (wikipedia.org)
- The researchers found that TDP-43 binds to U6 snRNA, apparently stabilizing the U6 snRNA molecules. (eurekalert.org)
- Because it binds to DNA, it presumably helps regulate gene expression, though its specific functions are largely unknown. (medpagetoday.com)
Found that TDP-431
Show that TDP-431
Levels of TDP-431
Targets of TDP-432
- Using a high-throughput sequencing approach combined with cross-linking immunoprecipitation (HITS-CLIP), direct targets of Tdp-43 have been identified ( 18 , 19 ). (sciencemag.org)
- In 2011, this team of UC San Diego scientists discovered that more than one-third of the genes in the brains of mice are direct targets of TDP-43, affecting the functions of these genes. (ucsd.edu)
Aggregation of TDP-431
- Pathological TDP-43 is abnormally ubiquitinated, hyperphosphorylated, and N-terminally cleaved to generate CTFs ( 4 , 5 ). (pnas.org)
- Pathological modifications of TDP-43 include proteolytic fragmentation, phosphorylation, and ubiquitinylation. (medworm.com)
- TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD. (wikipedia.org)
- The discovery of TDP-43 as the pathological link between mechanisms of nervous system degeneration in both ALS and FTLD opened up new opportunities for drug discovery as well as biomarker development for these disorders," says Lee. (scienceblog.com)
- Since chronic stress is associated with neurodegenerative diseases, the TDP-43 switch could be kept in overdrive mode in these disorders, with its capacity to buffer further stress and maintain protein homeostasis being compromised. (prolekarniky.cz)
- Further, TDP-43 is a signature protein in one subtype of frontotemporal degeneration, FTLD-U. Currently, there are no effective drugs for these neurodegenerative diseases. (sdbonline.org)
- Neurodegenerative diseases are characterized by cytoplasmic localization of TDP-43 in granule types. (padiracinnovation.org)
- In neurodegenerative diseases, TDP-43 is localized in the cytoplasm as well as in mitochondria that may be free in the cytoplasm or anchored in the endoplasmic reticulum, where it gives it the "raw" appearance of the endoplasmic reticulum. (padiracinnovation.org)
- For the first time, researchers at the University of Zurich have demonstrated a surprising effect of microglia, the scavenger cells of the brain: If these cells lack the TDP-43 protein, they not only remove Alzheimer's plaques, but also synapses. (medicalnewstoday.com)
- TDP-43 also is tied to minor neurodegenerative disorders and, in a recent discovery, is present in many Alzheimer's disease patients, as well. (slu.edu)
- Amador-Ortiz C, Lin WL, Ahmed Z et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. (springer.com)
- Arai T, Mackenzie IR, Hasegawa M et al (2009) Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies. (springer.com)
- Abnormalities of TDP-43 also occur in an important subset of Alzheimer's disease patients, correlating with clinical and neuropathologic features indexes. (wikipedia.org)
- Given the recent evidence that TDP-43 also accumulates in Alzheimer's disease, understanding the role of TDP-43 is all the more urgent," he said. (brown.edu)
- A mitochondrial TDP-43 inhibitory peptide may attenuate the progression of Alzheimer's disease in the 5XFAD transgenic mouse model. (padiracinnovation.org)
- A scientific article published on October 30, 2019 about Alzheimer's disease confirms the effect of a peptide against the aggregation of TDP-4 in mitochondria. (padiracinnovation.org)
- We provide the first experimental evidence that TDP-43 continuously shuttles between nucleus and cytoplasm in a transcription-dependent manner. (biologists.org)
- We also demonstrate that TDP-43 redistribution from the nucleus to the cytoplasm is sufficient to induce cytotoxicity. (uzh.ch)
- Furthermore, we determined that a pathogenic mutation in TDP-43 promotes redistribution to the cytoplasm and enhances the genetic interaction with VCP. (uzh.ch)
- Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and, thus, plays an important role in the early phase of insulin secretion by pancreatic islets. (jci.org)
- We also demonstrate that endogenous TDP-43 and FUS do not have overlapping functions in this cellular process as SG initiation and assembly occur normally in the absence of FUS. (molecularneurodegeneration.com)
- Furthermore, we investigate the role of the functional TDP-43 domains in determining cellular targeting through a combination of immunofluorescence and biochemical fractionation methods. (biologists.org)
- Our results provide insight into how the v-ATPase regulates mTORC1, and reveal a unique approach for enhancing cellular clearance based on covalent inhibition of lysosomal mTORC1 signaling. (nature.com)
- Signal peptide peptidase-like 3 (SPPL3) is a type II membrane protein-selective sheddase that regulates cellular N-glycosylation. (uni-muenchen.de)
- Chaperones display dynamic responses to exogenous and endogenous stressors and thus constitute a key component of the proteostasis network (PN), an intricately regulated network of quality control and repair pathways that cooperate to maintain cellular proteostasis. (biologists.org)
- Cellular oxidation/reduction (redox) states regulate various aspects of cellular function and maintain homeostasis [ 1 ]. (hindawi.com)
- TDP-43 is a multifunctional protein with many known cellular roles. (neurodegenerationresearch.eu)
- VCP (p97 in mouse, TER94 in Drosophila melanogaster, and CDC48 in Saccharomyces cerevisiae) is a highly conserved AAA(+) (ATPases associated with multiple cellular activities) ATPase that regulates a wide array of cellular processes. (uzh.ch)
- Budini M, Baralle FE, Buratti E. Regulation of gene expression by TDP-43 and FUS/TLS in frontotemporal lobar degeneration. (medlineplus.gov)
- Loss of shaggy /GSK3, hat-trick , or xmas-2 does not suppress Wallerian degeneration, arguing TDP-43(Q331K)-induced and Wallerian degeneration are genetically distinct processes. (sdbonline.org)
- With the discovery that our human stem cell model had predicted exactly what was happening in patients, Joe went on to test in this system whether fixing Stathmin2 could rescue the motor neuron degeneration in our dish caused by disturbing TDP-43. (harvard.edu)
- At the same time, notes Lee, "We soon will launch studies of novel strategies to prevent TDP-43-mediated nervous system degeneration using this mouse model of ALS and FTLD. (scienceblog.com)
- Endocytosis regulates TDP-43 toxicity and turnover. (alzforum.org)
- In addition to delineating genetic factors that modify TDP-43 toxicity, these results establish the Drosophila adult leg as a valuable new tool for the in vivo study of adult MN phenotypes. (sdbonline.org)
- The 2016 study directly linked the toxicity of TDP-43 to mitochondrial metabolism and proposed targeting the mitochondrial localization of TDP-43 as a promising therapeutic approach for ALS. (padiracinnovation.org)
- The PM1 synthesized peptide (YGRKKRRQRRRAQFPGACGL) in which the M1 motif was fused to the TAT peptide (GRKKRRQRRR), competitively inhibits the mitochondrial localization of TDP-43 and suppresses the TDP-43 induced toxicity on mitochondria. (padiracinnovation.org)
- This led the researchers then to examine the function of these risk genes in microglia cells - and made a discovery: If they turned off the gene for the TDP-43 protein in these scavenger cells, these cells remove β-amyloid very efficiently. (medicalnewstoday.com)
- C9orf72 , SOD1 , TDP-43 and FUS are ranked as the four major genes causing familial ALS. (nature.com)
- FUS and TDP-43, as well as other ALS-related genes, have also a recognized role in the regulation of RNA metabolism, including RNA transcription and splicing, microRNA processing and mRNA stability, transport and translation (thoroughly reviewed in Ratti and Buratti, 2016 ). (frontiersin.org)
- It regulates many genes and controls the processing of messenger RNA. (slu.edu)
- The TDP-43 protein was found to target over one-third of the genes in modeled mouse brains. (neurosciencenews.com)
- The genes most affected had numerous TDP-43 binding sites on very long introns, which are typically longer in genes from central nervous system tissue than genes from other tissues. (neurosciencenews.com)
- The JCI study showed that a dramatic loss of function causes nerve-cell death because normal mouse TDP-43 is eliminated when human mutated TDP-43 genes are put into the mice. (scienceblog.com)
- Next steps, say the researchers, will be to look for the specific genes that are regulated by TDP-43 and how mRNA splicing is involved so that the abnormal regulation of these genes can be corrected. (scienceblog.com)
- The study resulted in a list of genes that are up or down regulated, and the researchers duplicated the findings in human cells. (ucsd.edu)
- Furthermore, G3BP can rescue defective SG assembly in cells depleted of endogenous TDP-43. (molecularneurodegeneration.com)
- By contrast, we engineered a construct that includes only the specific TDP-43 amino acid sequences necessary to trigger aggregate formation and capable of trapping endogenous Drosophila TDP-43 into a non-functional insoluble form. (biologists.org)
- Recently, it has been demonstrated that zinc ions are able to induce aggregation of endogenous TDP-43 in cells. (wikipedia.org)
- The TDP-43 ELISA kit is to be used to detect and quantify protein levels of endogenous TDP-43. (ptglab.com)
Findings suggest that TDP-431
- Recently, overexpression of the TDP-43 homolog in yeast or injections of viral hTDP-43 constructs in the substantia nigra of rats have been shown to cause cell death ( 14 , 15 ). (pnas.org)
- TDP-S6 overexpression caused a concomitant increase in both ubiquitin (Ub) and the small Ub-like modifier-2/3 (SUMO-2/3) within the insoluble proteome. (mcponline.org)
- Similarly, full-length TDP-43 overexpression also resulted in the elevation of SUMO-2/3. (mcponline.org)
- Our fly model is not based on the overexpression of a wild-type TDP-43 transgene. (biologists.org)
- Next, we showed that an increase and/or overexpression of the cytoplasmic TDP-43 drives the pathogenic NF-κB response and further increases levels of pro-inflammatory markers and ischemic injury after stroke in age-dependent manner. (biomedcentral.com)
- Moreover, the role of wild-type (WT) TDP-43, associated with the majority of familial and sporadic ALS/FTLD patients, is also currently unknown. (pnas.org)
- In addition, TDP-43 undergoes proteolytic cleavage by caspase-3 to generate 25- and 35-kDa fragments when GRN (granulin/PGRN) (a candidate gene for familial FTLD-U) is down-regulated. (sigmaaldrich.com)
- Dose-Dependent Motor Neuron Disease in TDP43 WT Mice. (pnas.org)
- In particular, presence of TDP-43 affects the exon usage of the cystic fibrosis transmembrane regulator (CFTR), apolipoprotein A-II, and survival of motor neuron (SMN) transcripts ( 14 - 16 ). (pnas.org)
- This study describes the generation and characterization of a new fly model of ALS-TDP with transgenic expression of the Drosophila ortholog of TDP-43, dTDP, in adult flies under the control of a temperature sensitive motor neuron-specific GAL4, thus bypassing the deleterious effect of dTDP during development. (sdbonline.org)
- Once we had a connection between the TDP-43 and the loss of this other critical gene, STMN2 , we could see how a motor neuron might begin to fail in ALS," said Joseph Klim , postdoctoral fellow in the Harvard Department of Stem Cell and Regenerative Biology (SCRB). (harvard.edu)
Absence of TDP-431
Gene coding for1
Role for TDP-432
Indicate that TDP-431
Localization of TDP-432
- Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. (jci.org)
- The mitochondrial localization of TDP-43 is dependent on its M1 motif, the deletion of which suppresses its mitochondrial accumulation. (padiracinnovation.org)
- Moreover, the characteristic ≈25-kDa C-terminal fragments (CTFs) were also recovered from nuclear fractions and correlated with disease development and progression in WT TDP-43 mice. (pnas.org)
- For example, the TDP-43 knockout mice die in early embryogenesis, making it difficult to tease out the physiological functions of the protein. (asbmb.org)
- The C-terminal tail of TDP-43 does not bind RNA but is necessary to modulate the splicing of CFTR exon 9, probably through the recruitment of an hnRNP complex. (biologists.org)
- In fact, TDP-43 associates with hnRNP A isoforms (i.e. hnRNP A1 and hnRNP A2/B1) through this region specifically. (biologists.org)
- hnRNP-U inhibits TDP-43-mediated alterations in splicing of POLDIP3 mRNA. (antibodies-online.com)