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 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 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 (ATP) and EC (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.
... and is found depleted in the nucleus. In addition to ALS/MND and FTLD-U, TDP-43 pathology is a feature of many cases of ... This finding is in contrast to studies that found minimally infectious prions produced from recombinant PrP alone. In 2012, ... The protein that prions are made of (PrP) is found throughout the body, even in healthy people and animals. However, PrP found ... Specifically, aggregation of TDP-43, an RNA-binding protein, has been found in ALS/MND patients, and mutations in the genes ...
He has also developed a series of compounds that potently and effectively inhibit TDP-43 aggregation in multiple neuronal ... Wolozin combined forces with Glenn Larsen, Ph.D. to co-found the biotechnology company, Aquinnah Pharmaceuticals. Aquinnah ... TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue". PLoS ONE. 5 (10). doi: ...
One study found that glucose metabolism was decreased in schizophrenics, while another found abnormal glucose metabolism that ... For example, when the proteins amyloid-b and TDP-43 are in their abnormal form, they spread trans-synaptically and are ... They also found that greater damage to the cingulum bundle, that connects the PCC to the anterior DMN, was linked to ... Recently it was found that the psychedelic drug psilocybin induces an altered state of consciousness and is related to abnormal ...
It was found that certain CCNF mutations caused increased ubiquitination of TDP-43 protein in cells, which is a major feature ... It is found most abundantly in the nucleus, and the quantity levels vary during the different stages of cell cycle. Its ...
Following up on earlier leads, the Greenberg group report finding that the protein TDP-43 is a very prominent and highly ... This protein is normally found within the nucleus but in IBM is found in the cytoplasm of the cell. This important advance ... The authors found that the current prevalence was 14.9 per million in the overall population, with a prevalence of 51.3 per ... 2009). "Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis". Muscle Nerve. 40 (1): 19-31. doi:10.1002/mus ...
The company was co-founded in 2002 by the late gynecologist, surgeon and venture capitalist K. M. Seng and Claude Wischik, ... Their lead compound, LMTX, targets aggregation of tau and is believed to act on synuclein, TDP-43 and huntingtin protein. Its ...
Beyond nucleic acid binding, FUS/TLS was also found to associate with both general and more specialized protein factors to ... Mackenzie IR, Rademakers R, Neumann M (October 2010). "TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal ... In 2009 two separate research groups analysed 26 unrelated families who presented with a type6 ALS phenotype, and found 14 ... but not for TDP-43 or tau with a proportion of the inclusions also containing a-internexin in a further subgroup known as ...
Discoveries by the centre include the finding that Zebrafish are able to produce motor neurones when they repair their spinal ... cords from injury and abnormalities in the protein TDP-43 result in the death of motor neurone cells. "About The Euan MacDonald ...
In 1998 it founded a third institute dedicated to studying neurological diseases. In 2004 the Gladstone Institutes moved to a ... Studying TDP-43, another protein that may contribute to diverse neurodegenerative disorders. Protein aggregates and their role ... Founded in 1979, Gladstone is affiliated with the University of California, San Francisco (UCSF) and is located in San ... Gladstone Institutes was founded in 1979 as a research and training facility housed at San Francisco General Hospital. Under ...
Several conserved domains have been found in UNC13A. These conserved domains include three C2 domains. One C2 domain is ... Pathology involving TDP-43 is a result of the single nucleotide polymorphisms in both ALS and FTD. This gene has also been ...
The protein is found in many regions of the brain, in the cytoplasm of neurons as well as in presynaptic terminals. Disease ... It is currently the most common demonstrated mutation related to ALS - far more common than SOD1 or TDP-43. While different ... Since this mutation has been found to be the most common mutation identified in familial FTD and/or ALS, it is considered one ... Some studies have found that the mutation has a higher frequency in certain cohorts. Athena Diagnostics (Quest Diagnostics) ...
The TDP-43 protein, coded for by the TARDBP gene, is responsible for regulation of RNA expression. The discovery of mutations ... The most common mutation found in Scandinavian countries, D90A-SOD1, is more slowly progressive than typical ALS, and people ... SOD1 and TDP-43 mutations may play a role in causing mitochondria dysfunction. Increased markers of oxidative stress have been ... a genetic abnormality known as a hexanucleotide repeat was found in a region called C9orf72, which is associated with ALS ...
With the discovery that TDP-43, FUS, and C9orf72 can cause ALS as well as related forms of frontotemporal dementia (FTD/ALS)[ ... One study found that NIV is ineffective for people with poor bulbar function[96] while another suggested that it may provide a ... This led to the discovery in 2008 that mutations in TARDBP, the gene that codes for TDP-43, are a cause of familial ALS.[22] In ... A 2015 review found that moderate to severe traumatic brain injury is a risk factor for ALS, but whether mild traumatic brain ...
found that low SES, indexed by poor education and lack of home ownership, was a risk factor for epilepsy in adults, but not in ... It has been linked to abnormalities in TDP-43. Sommer, W (1880). "Erkrankung des Ammon's horn als aetiologis ches moment der ... Although hippocampal sclerosis is relatively commonly found among elderly people (≈10% of individuals over the age of 85 years ... Hippocampal sclerosis is a frequent pathologic finding in community-based dementia. Hippocampal sclerosis can be detected with ...
A 2016 Cochrane review of cell based therapies found that there was insufficient evidence to speculate about efficacy. Stem ... The TDP-43 transgenic mouse model was also used for ALS studies and it shows similar results to the SOD1 expression, which ... One 2016 review of stem cell therapy trials found tentative evidence that intraspinal stem cell implantation was relatively ... and they found that the functional genes and the ER stress regulating genes of the mitochondria were reduced in SOD-1 patients ...
Another study from 2012 also found a possible increase in ALS in NFL football players. An older study did not find an increased ... TDP-43, or TARDBP), or FUS. The mutant SOD1 may also contribute to motor neuron cell death through generating free radicals. ... A 2007 review found an increased risk among soccer players. ALS may also occur more often among the US military veterans ... The judge in the case concurred, and the NFL then agreed to pay an unlimited amount of damages for players found to have ALS, ...
Essentially, it was found that superordinate knowledge of music, such as the rules of composition, may be more robust than ... TDP-43 positive, tau-negative inclusions, although other pathologies have been described more infrequently, namely tau-positive ... Rohrer, J.D.; Knight, W.D.; Warren, J.E.; Fox, N.C.; Rossor, M.N.; Warren, J.D. (January 2008). "Word-finding difficulty: a ... Speech of SD patients is marked by word-finding pauses, reduced frequency of content words, semantic paraphasias, ...
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 ... "Antiviral protein APOBEC3G localizes to ribonucleoprotein complexes found in P bodies and stress granules". Journal of Virology ... Colombrita C, Zennaro E, Fallini C, Weber M, Sommacal A, Buratti E, Silani V, Ratti A (November 2009). "TDP-43 is recruited to ... Aulas A, Vande Velde C (2015). "Alterations in stress granule dynamics driven by TDP-43 and FUS: a link to pathological ...
They also found that greater damage to the cingulum bundle, that connects the PCC to the anterior DMN, was correlated with ... when the proteins amyloid-b and TDP-43 are in their abnormal form, they spread across synapses and are associated with ... 2011) found that patients with ADHD exhibit an increased left PCC,[20] suggesting that developmental abnormalities affect the ... In a subsequent study, it was found that TBIs are related to a difficulty in switching from automatic to controlled responses.[ ...
465(7295): p. 223-6. Roeber, S., et al., TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD. Acta ... Founded as a start-up company in Chicago in 2002, it supplies polyclonal and monoclonal antibodies to the medical and life ... 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 ...
The founding conference was held at Salem, Tamil Nadu in May 1989. Delegates from Tamil Nadu, Andhra Pradesh, W. Bengal, Orissa ... Jagannadham won with a majority of approximately 700 votes over his nearest rival from the TDP party. Five years he have served ... Late S.A. Dange, the founding leader of CPI S.A. Dange Late Mohit Sen, the founder of erstwhile Indian Communist Party D. ... a senior founding leader from Kerala. Ramesh Sinha Wadhawa Ram S.U. Palanisamy Dev Kumar Yadav K.M. Sundram K. Manikam Keshav ...
A similar compound is lanthionine, which can be seen as two alanine molecules joined via a thioether bond and is found in ... Implications for protein misfolding and TDP-43 regulation". Journal of Neuroscience Research. 89 (9): 1471-1477. doi:10.1002/ ... In biochemistry, non-coded or non-proteinogenic amino acids are those not naturally encoded or found in the genetic code of any ... All 22 proteinogenic amino acids are biosynthesised by organisms and some, but not all, of them also are abiotic (found in ...
Oedema may be found in the regions surrounding the third ventricle, and fourth ventricle, also appearing petechiae and small ... Thiamine is first metabolised to its more active form, thiamine diphosphate (TDP), before it is used. The body only has 2-3 ... In a series of autopsy studies held in Recife, Brazil, it was found that only 7 out of 36 had had alcoholic habits, and only a ... The classic triad of symptoms found in Wernicke encephalopathy is:[7]. *ophthalmoplegia (later expanded to other eye movement ...
These results, found by probing with immunoassays, have been challenged by studies that interrogate DNA sequence by bisulfite ... Dewey CM, Cenik B, Sephton CF, Johnson BA, Herz J, Yu G. "TDP-43 aggregation in neurodegeneration: are stress granules the key ... There may be some effect of age in levels of DNA methylation at specific gene promoters, as one study found greater levels of ... Acetylation occurs on the lysine residues found at the amino N-terminal of histone tails. Histone acetylation is most commonly ...
... ... The short-wave transmitters are located at Zygi 34°43′18″N 33°19′27″E / 34.72167°N 33.32417°E / 34.72167; 33.32417. The ...
"Find a County". National Association of Counties. Archived from the original on May 31, 2011. Retrieved June 7, 2011.. ... and some of the 20 projects TDP lists have not broken ground and are being refinanced. Nonetheless several developments were ... "Hull of Civil War sloop likely found in Tampa river - St. Petersburg Times". Tampa Bay Times. Retrieved February 23, 2010.. ... The University of Tampa (UT) is a private, four-year liberal arts institution.[157] It was founded in 1931, and in 1933, it ...
From this, they found that the protein CAS is found in lesser quantities than normal for people who have FTD but did find any ... Finding the key to why TDP-43 accumulates in MND. Posted on June 10, 2010. by Kelly Edwards ... The search will now continue to find out what causes TDP-43 to go wrong in MND which may lead to the discovery of a new target ... The two proteins that were found to cause an accumulation of TDP-43 outside of the nucleus are called CAS (which stands for ...
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Anti-TDP-43 immunohistochemistry and the recent development of novel tools, such as phosphorylation-specific TDP-43 antibodies ... This review summarizes the recent advances in our understanding on the molecular neuropathology and pathobiology of TDP-43 in ... The identification of TDP-43 as the major component of the pathologic inclusions in most forms of sporadic and familial ... Find support for a specific problem on the support section of our website. ...
Lastly, FUS/TLS, another ALS-linked protein (9, 10), was found associated with TDP-43. Although less than 1% of wild-type FUS/ ... TDP43G298S, TDP43Q331K, and TDP43M337V), we showed that all three of these ALS-linked mutations exhibit longer protein half- ... All of the proteins whose peptides were found to be TDP-43-associated in the SILAC mass-spectrometric analyses, the TDP-43 ... Preferential ALS-Linked Mutant TDP43 Association with FUS/TLS.. Discovery of FUS/TLS, another ALS-linked gene product, in TDP- ...
... its fragments GFP-TDP-35 or GFP-TDP-25 for 48 h. Under similar conditions, we found that TDP-43, TDP-35, and TDP-25 increased ... Levels of TDP-35 and TDP-25 or p-TDP-43 significantly increased in the cervical (C) and lumbar (L) spinal cord of fALS patient ... MTSOD1 transfected cells had significantly higher level of TDP-35 and TDP-25. b Western blots with anti-GFP or anti-TDP-43 ... TDP-25, and human SOD1 than WT mice. g At 120-days, the levels of TDP-35 and TDP-25 were significantly increased in hSOD1G93A ...
2014) found aggregated and phosphorylated TDP-43 in the neuronal somata of affected cells, but not in the axons of neurons that ... rAAV-TDP-L2, and rAAV-TDP-Luc were constructed by cloning TDP-L1 and TDP-L2 into XhoI-EcoRV sites of the AAV-CBA-WPRE vector. ... or TDP-L1 + TDP-L2. n = 10 per group. Mean ± SEM. ****, P , 0.0001. (D) SEC of cell lysates derived from TDP-L1 + TDP-L2- ... CM was obtained from HEK-293 cells transfected either with mock, TDP-L1 + TDP-L2, or TDP-Luc. n = 4 per group. (C) Luciferase ...
Scientists expect to elucidate pathogenic mechanisms of Frontotemporal Dementia (FTD) and other diseases once they find how Tdp ... If Tdp-43 is normal, it will repress the expression of a specific cryptic exon and produce a normal protein; however, when a ... Abnormal proteins found in cells are formed by interlacing of cryptic exons, so they are unstable in terms of structure or are ... Variable Tdp-43 cryptic exons between cell types International research team including the Korea Brain Research Institute found ...
They found some 130,000 sites where TDP-43 could target-not surprising, Ule said, given that TDP-43 binds to UG repeats, the ... Among TDP-43s most tantalizing targets are the FTLD-related genes FUS and progranulin, TDP-43 itself, the glutamate ... The researchers found more than 10,000 transcripts that bound TDP-43. They noticed that TDP-43 in FTLD samples was more likely ... When they examined their data quantitatively, the MRC scientists found that TDP binding to many transcripts was up- or ...
TDP43 or TARDBP) - Pipeline Review, H2 2016, provides in depth analysis on TAR DNA Binding Protein 43 (TDP43 or TARDBP) ... TDP43 or TARDBP), targeted therapeutics, complete with analysis by indications, stage of develo ... The report provides comprehensive information on the TAR DNA Binding Protein 43 ( ... We will be happy to help you find what you need. Please call us or write to us:. 866-997-4948. (US-Canada Toll Free). Tel : +1- ...
We find that disruption of the nucleic-acid-binding ability of TDP-43 or removal of its C-terminal tail interfere with the ... In agreement with previous studies (Abhyankar et al., 2007) we found that endogenous TDP-43 accumulated in the nucleoplasm and ... Find out more and apply for your place here.. Journal news - New fast-track decision process. Do you have a paper with reviews ... TDP-43 comprises two RNA recognition motifs (RRMs) followed by a glycine-rich C-terminal domain. The presence of the RRMs is a ...
7A). Interestingly, the drop in expression was found at all three time points assayed (day 3, 7 and 11), in agreement with the ... 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 ...
SUMO-2/3 was found to be preferentially enriched within the TDP-43 and TDP-S6 insoluble proteomes and was subsequently ... 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 ...
The authors find only initial co-localization of this mutant with stress granules. At later time points, TDP-43 separates and ... The finding that TDP-43 can remain in dynamic liquid droplets for extended periods of time that are nonetheless toxic also ... In each, she found that normal TDP-43 formed droplets in the nucleus that dynamically fused and broke apart, rapidly exchanging ... Gasset-Rosa found that the cytoplasmic TDP-43 droplets appeared to be toxic. Initially, they didnt kill cells, but after about ...
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 ... ... We found that poly(PR) bound DNA, localized to heterochromatin, an.... Source: ScienceNOW - February 14, 2019. Category: ...
Interestingly, no MAPT mutations have been found in Alzheimer disease.. FTLD-U, Progranulin mutations, TDP-43, and FUS ... A study by Mesulam et al found no association between FTD and the APOE-4 genotype. [44] Other studies have had somewhat ... Rather, an accumulation of "fused in sarcoma" (FUS) proteins have been found. Reported cases have included both FTD and ALS. [ ... Urwin H, Josephs KA, Rohrer JD, Mackenzie IR, Neumann M, Authier A. FUS pathology defines the majority of tau- and TDP-43- ...
TDP-43) was identified as the major disease protein in frontotemporal lobar... ... No association was found between a history of single TBI and abnormally phosphorylated TDP-43 (p-TDP-43) inclusions. ... now termed FTLD-TDP, and amyotrophic lateral sclerosis (ALS). More recently, TDP-43 proteinopathy has been reported in dementia ... TDP-43 43 kDa transactive response (TAR) DNA binding protein Traumatic brain injury Head injury Diffuse axonal injury DAI ...
We found that ubiquitin-specific protease 7 (USP7 also known as HAUSP) associates with CRY1 and CRY2 and stabilizes CRYs ... TDP-43 stabilized CRY1 and CRY2, and its knockdown also shortened the circadian period in cultured cells. The present study ... identified USP7 and TDP-43 as the regulators of CRY1 and CRY2, underscoring the significance of the stability control process ... We identified another CRYs-interacting protein, TAR DNA binding protein 43 (TDP-43), an RNA-binding protein. ...
Recently, the major disease protein found in the pathological inclusions of two of these diseases, amyotrophic lateral ... 3I). TDP-43-YFP inclusions also did not stain positive for the amyloid-binding dye thioflavin T (Fig. S4). These results are ... 3 E and G and data not shown), these manipulations had no effect on either the localization or the toxicity of TDP-43 (Fig. 3 F ... 2007) TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J Neuropathol Exp Neurol 66:152-157 ...
We also find that TDP-43 cytoplasmic aggregation impairs TDP-43 function in R-loop regulation. Furthermore, increased R-loop ... Find out more about both roles.. Author choices on Journal of Cell Science: how open are we to Open Access. Read our ... TDP-43 loss increases DNA damage and compromises cell viability, but the actual function of TDP-43 in preventing genome ... TDP-43 nucleic-acid binding and self-assembly activities are important in inhibiting R-loop accumulation and preserving normal ...
Lastly, we found that TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in ... The second CLIP cluster (middle purple-outlined box) with weak binding was found only when relaxing cluster-finding algorithm ... Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43.. Polymenidou M1, Lagier- ... TDP-43 isoform 3 was increased in response to elevated TDP-43 protein levels, blocking of NMD (by UPF1 siRNA) and there was a ...
Information on how to subscribe to Neurology and Neurology: Clinical Practice can be found here ... FTLD-TDP. frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions. FUS. fused in sarcoma. MMSE. Mini-Mental ... Conclusions: FTLD-TDP subtypes have distinct clinical and neuroimaging features, highlighting the relevance of FTLD-TDP ... TDP-43 subtypes are associated with distinct atrophy patterns in frontotemporal dementia. J.D. Rohrer, F. Geser, J. Zhou, E.D. ...
"This is an important finding as genes expressed in the central nervous system have much longer introns than genes expressed in ... The TDP-43 protein was found to target over one-third of the genes in modeled mouse brains. The genes most affected had ... The loss of TDP-43 removes this check; more TDP-43 is generated and more is likely to accumulate in the cytoplasm." ... 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 ...
TDP-43) - Pipeline Review, H1 2016 report by Global Markets Direct. Global Markets Directs, TAR DNA-Binding Protein 43 (TDP ... 46 Pages Report] Check for Discount on TAR DNA-Binding Protein 43 ( ... Did you find what you are/were looking for ? If not, read below and browse through other relevant pages for similar market ... Small Molecule to Inhibit TDP-43 for Amyotrophic Lateral Sclerosis - Drug Profile 26 Product Description 26 Mechanism Of Action ...
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 ...
We also found decreased Fe65 expression. A parallel increase in AICD expression was not found. Patients showed increased ... The latter was correlated with cytoplasmic pho-TDP-43 expression. We also found decreased Fe65 expression. A parallel increase ... The latter was correlated with cytoplasmic pho-TDP-43 expression. ... pho-TDP-43, Aβ, AICD peptide, Fe65 protein, and pho-TAU in the hippocampus of 7 patients with ALS, 2 patients with ALS-FTD, and ...
  • 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. (
  • 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. (
  • 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 ). (
  • The results bolster the idea that liquid TDP-43 droplets form in early stages of disease, then yield gels or solids as pathology worsens, suggested Gasset-Rosa. (
  • This process may be central to understanding the emergence of TDP-43 pathology," wrote Yuna Ayala, St. Louis University, who was not involved in the research (see full comment below). (
  • 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). (
  • Specifically, just 3 of 62 TBI cases displayed p-TDP-43 pathology versus 2 of 47 control cases. (
  • Four patients had too sparse FTLD-TDP pathology to be subtyped. (
  • However, TDP-43 is unable to silence jumping genes when it is growing in clumps in nerve cells, and by studying gene expression in brain tissue samples from post-mortem ALS patients, both with and without TDP-43 pathology, they found that jumping genes were not silenced as extensively in patients with high levels of TDP-43 proteins. (
  • These jumping genes are telling us about patients who have TDP-43 pathology. (
  • We found that lowering levels of ataxin 2 in mouse, either by knockout or with antisense oligonucleotides (ASOs) can markedly extend survival and reduce pathology in TDP-43 transgenic mice (Becker et al. (
  • 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. (
  • 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. (
  • TDP-43 pathology was present in 11 patients (33.3%), including components in both basal forebrain (n= 10) and hypothalamus (n= 7). (
  • 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. (
  • Furthermore, TDP-43 pathology in the lateral hypothalamic area was associated with reduced body mass index (W= 11, p= 0.023). (
  • Analysis involved assessing 43 kDa Tar-DNA binding protein (TDP-43) accumulation in brain regions specifically involved in executive functions, language functions and verbal fluency to ascertain whether functional deficits would relate to a specific regional distribution of pathology. (
  • The ECAS also predicted TDP-43 pathology with 100% specificity in brain regions associated with executive, language and fluency domains. (
  • We also detected a subgroup with no cognitive dysfunction, despite having substantial TDP-43 pathology, so called mismatch cases. (
  • Conclusions Cognitive impairment as detected by the ECAS is a valid predictor of TDP-43 pathology in non-demented ALS. (
  • At the same time, working together with Assistant Professor Molly Hammel at Cold Spring Harbor Laboratory, the Dubnau lab discovered that human protein TDP-43 binds to the RNAs produced by transcription of transposable elements, and that this binding is selectively disrupted in brain tissue of patients with a type of dementia that frequently presents with TDP-43 pathology. (
  • But does this TDP-43 pathology actually cause a transposon storm, neuronal cell death, and ultimately mortality? (
  • The major aim of Lisa's thesis was to test whether modeling the ALS-associated TDP-43 protein pathology in the fly brain would disrupt transposon suppression and cause the symptoms of neurodegeneration similar to those seen in old flies-and in ALS patients. (
  • Our previous observations regarding TDP-43's interactions with transposon targets in human ALS data led us to be quite confident that TDP-43 pathology might disrupt transposon expression in flies," said Lisa. (
  • We want to see whether TDP-43 pathology induces high levels of transposon expression and if this causally contributes to reductions in lifespan and cell death. (
  • As Lisa explained, "While ALS presents in all different types of people with no known genetic predictor, understanding how and why cells die in response to TDP-43 pathology, which occurs in almost all ALS cases, is arguably one of the most direct methods by which to develop successful therapies. (
  • No signs of TDP-43 or other pathology like that of the athletes were seen in any of the normal controls. (
  • Importantly, a quantitative analysis comparing the morphology of cortical TDP-43 pathology in FTLD, FTLD-ALS and ALS cases has not been performed. (
  • 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. (
  • Jessell thinks that the ability to quickly test ideas-in months, not years-about the underlying pathology of ALS is key to finding that central idea. (
  • The study showed that as TDP-43 accumulates in the brain of patients with FTLD, it ropes in DISC1, an important protein in the pathology of many mental conditions. (
  • A new study, published today in Neuron , shows how TDP-43 pathology can be recreated in the lab, and how an oligonucleotide - a short strand of RNA - made to mimic cells' natural protective mechanism can rescue neurons from TDP-43 accumulation. (
  • First, Donnelly and his team had to reproduce TDP-43 pathology in cultured human cells - a "disease in a dish" - so they developed a system that uses light pulses to push these proteins together into poisonous little balls. (
  • The tau-negative, TDP-43 positive variant is considered to be the most common underlying pathology for frontotemporal lobe degeneration (FTLD) ( 10 ). (
  • TDP-43 pathology is also commonly associated with hippocampal sclerosis, the severe shrinkage of the hippocampal region of the brain - the part of the brain that deals with learning and memory . (
  • We show that TDP-43 is also a 'perpetrator', in that it can cause transport defects on its own in most ALS cases, and potentially other neurodegenerative diseases with TDP-43 pathology, such as frontotemporal dementia," he says. (
  • TDP43 pathology is seen in about 98 percent of ALS cases and about 50 percent of FTD cases, and our work supports the now-accepted conclusion that nucleopore abnormalities are not restricted to C9orf72 expansion mutations," Glass says. (
  • The research group first silenced (quite literally stopping the function) 82 proteins that are known to be involved with the transport of cargo, such as TDP-43 into the nucleus. (
  • From this they identified five proteins that when silenced result in an accumulation of TDP-43 outside of the nucleus. (
  • The two proteins that were found to cause an accumulation of TDP-43 outside of the nucleus are called CAS (which stands for Cellular Apoptosis Susceptibility) and Karopherin-β1. (
  • They then went on to see whether the levels of these two proteins are altered in people who have sporadic ALS (the most common form of MND) with TDP-43 clumps (so called TDP-43 positive) or TDP-43 positive FTD. (
  • 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. (
  • 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. (
  • Moreover, it is rare to find a connection between proteins in the pathological mechanism involved in ALS. (
  • Tdp-43 is a protein that regulates the process of making proteins from genes. (
  • These are liquid droplets of RNA and RNA-binding proteins, including TDP43, that temporarily form when cells are under duress. (
  • Massively parallel sequencing and splicing-sensitive junction arrays revealed that levels of 601 mRNAs were changed (including Fus (Tls), progranulin and other transcripts encoding neurodegenerative disease-associated proteins) and 965 altered splicing events were detected (including in sortilin, the receptor for progranulin) following depletion of TDP-43 from mouse adult brain with antisense oligonucleotides. (
  • RNAs whose levels were most depleted by reduction in TDP-43 were derived from genes with very long introns and that encode proteins involved in synaptic activity. (
  • 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. (
  • 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. (
  • 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. (
  • The new study, published in Cell Reports , analyzed the part TDP-43 proteins (so-called for their role in creating transactive response DNA binding protein 43 kDa) play in ALS. (
  • By analyzing the functions of TDP-43 proteins, which are found inside cell nuclei in most tissues, Hammell and her research team aimed to find out whether there were differences between patients' ALS cases. (
  • 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. (
  • The TDP-43 protein is involved in processing molecules called messenger RNA (mRNA), which serve as the genetic blueprints for making proteins. (
  • By cutting and rearranging mRNA molecules in different ways, the TDP-43 protein controls the production of different versions of certain proteins. (
  • Many of the proteins whose production is influenced by the TDP-43 protein are involved in nervous system and organ development. (
  • four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. (
  • They injected the molecules into mice to create antibodies capable of recognizing the various suspect proteins, and then searched through the antibodies to find those that stuck only to the clumps in brain samples of FTD patients. (
  • In short, the Penn researchers found that, in healthy mice, a single injection of synthetic, misfolded α-Syn fibrils led to a cell-to-cell transmission of pathologic α-Syn proteins and the formation of Parkinson's α-Syn clumps known as Lewy bodies in interconnected regions of the brain. (
  • 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. (
  • 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. (
  • Loss of TDP-43 led to changes in the levels of multiple other proteins, an effect which was also observed in part in the spinal cords of humans with ALS. (
  • These authors used two different screens to systematically look for proteins that when deleted or expressed at lower levels rescued yeast overexpressing TDP-43. (
  • We also found that binding of TDP-43 to pre-mRNAs influenced alternative splicing in a similar position-dependent manner to Nova proteins. (
  • Additionally, I found that both proteins have the same requirements for SG recruitment, as their main RNA-binding domain and a glycine-rich domain are essential for SG localization. (
  • 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. (
  • It turns out that proteins like the TDP-43, FUS and Ataxin-2 found in MND are also involved in the natural control and management of protein expression in the cell. (
  • At the mechanistic level, TDP-43 and DISC1 co-aggregation disrupted activity-dependent local translation in dendrites,' said Dr. Tanaka, a process that builds proteins from DNA codes based on neural activity. (
  • 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. (
  • Under blue light control, TDP-43 proteins aggregate inside the neuron and cause it to die. (
  • Baiting the TDP-43 proteins prevented aggregation and kept the cells from dying. (
  • Two proteins previously found to contribute to ALS, also known as Lou Gehrig's disease, have divergent roles. (
  • 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. (
  • They also found that mutant profilin accumulated in clumps in neural cells, as has been seen for other abnormal proteins associated with ALS, Parkinson's and Alzheimer's. (
  • 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). (
  • Ling said the research team was also working with experts on cancer and immunology to see if other proteins might perform similar roles as TDP-43, possibly leading to far broader implications. (
  • When TDP-43 clumps together, so do the nuclear pore proteins. (
  • He found that the clumping alters the shape of the nuclear membrane and the nuclear pores, and thus disrupts the import of proteins into the nucleus and export of RNA out of it. (
  • 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 ). (
  • 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. (
  • 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. (
  • The data uncovers autonomous and non-autonomous functions of TDP-43 in glia and suggests new experimentally based therapeutic strategies in ALS. (
  • To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. (
  • So Lisa produced flies that carried extra human TDP-43 in the fly brain and asked whether she could see the cellular phenotypes of ALS in the fly brain. (
  • In a previous study, the Stanford-led team had shown that when ataxin 2 is suppressed or blocked in yeast cultures and fruit flies that carry the human TDP-43 gene, cells are more resistant to the potential toxic effects of the clumping TDP-43 protein. (
  • We provide the first experimental evidence that TDP-43 continuously shuttles between nucleus and cytoplasm in a transcription-dependent manner. (
  • However, as described in another recent Neuron paper, Da Cruz and colleagues found that TDP43 condenses independently of stress granules in the cytoplasm of stressed cells. (
  • However, if the researchers treated human SH-SY5Y neuroblastoma cells with fibrils of either TDP-43 or FUS, TDP-43 drained out of the nucleus and accumulated in liquid droplets in the cytoplasm. (
  • The same droplets formed if the researchers overexpressed TDP-43 in the cytoplasm. (
  • Taken together, the results demonstrate that independently of stress granules, TDP-43 phase-separates in the cytoplasm in response to various stressors, and that this can both interfere with nucleocytoplasmic transport and siphon away nuclear TDP-43, resulting in cell death. (
  • This accumulation of TDP-43 occurs in the cytoplasm of cells, thereby depleting TDP-43 from the nucleus where it normally resides. (
  • Researchers like Gitler and Farese have been able to mimic the disease in yeast by expressing TDP-43 at higher-than-normal levels, which causes the protein to form lethal clumps in the cells' cytoplasm. (
  • The researchers note that it's still not entirely clear whether the cells die because the mutant TDP-43 is drawing essential RNA transcripts or regulatory molecules away from the nucleus and into the cytoplasm, or because it's not performing its normal RNA-binding function in the nucleus. (
  • One protein, TDP-43, has been found to accumulate in the cytoplasm of cells from patients with neurodegenerative disorders, including ALS. (
  • This study showed directly that the accumulated lariats interact with TDP-43 in the cytoplasm to suppress its toxicity. (
  • Understanding why TDP-43 moves to the cytoplasm and tends to aggregate or clump up there, and how those behaviours lead to the development of ALS, is a crucial area of investigation in ALS research. (
  • They discovered that the presence of TDP-43 in the cytoplasm caused the longer form to accumulate there as well. (
  • Insights from this project may also reveal hnRNPA1B as a target for the development of new therapies, such as a drug that could prevent or slow down its formation, and a biomarker to measure the effectiveness of a new drug designed to keep TDP-43 from moving out of the nucleus to the cytoplasm. (
  • She hypothesizes that when the C9ORF72 gene is mutated, it loses the ability to perform its normal functions, causing an accumulation of misplaced TDP-43 in the cytoplasm. (
  • The TDP-43 protein was mostly expressed and distributed in the nuclear of neuron cells and the cytoplasm of oligodendrocyte cells of the gray matter surrounding the central canal of spinal cord by the granular shape in the SOD1 wild-type and G93A transgenic mice. (
  • Similarly, full-length TDP-43 overexpression also resulted in the elevation of SUMO-2/3. (
  • However, we did not observe the same effect for full-length TDP-43. (
  • Using transgenic mice that overexpress the 25 kDa C-terminal fragment of TDP-43, here we show that glucocorticoids, stress hormones known to increase the brain susceptibility to neurotoxic insults, increase the levels of soluble TDP-25 and exacerbate cognitive deficits, without altering full-length TDP-43 levels. (
  • In this thesis I demonstrate that cytosolically mislocalized full-length TDP-43 is recruited into SGs, whereas C-terminal fragments of TDP-43 (TDP-CTFs) fail to localize to SGs. (
  • In a study published in Current Opinion in Neurology , authors write that the discovery of "elevated plasma levels of TDP-43, in some patients with neurodegenerative disease, supports the possible use of TDP-43 as an in vivo biomarker to aid in diagnosis and monitoring the effects of therapy. (
  • They found that higher levels of TDP-43 resulted in a loosening of the scaffold which reduced ER-mitochondria bonds,affecting some important cellular functions that are linked to ALS and FTD. (
  • Here, we show that loss of TDP-43 increases R-loop formation in a transcription-dependent manner and results in DNA replication stress. (
  • These important results tell us that loss of TDP-43 may contribute to the disease process and amplify previous findings on the importance of astrocytes in the disease process," said Lucie Bruijn, Ph.D., MBA, Chief Scientist for The Association. (
  • If further experiments confirm the role of loss of TDP-43, therapies that prevent TDP-43 aggregation, or replace its lost function, could be a valuable treatment approach. (
  • 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 ). (
  • We demonstrate the exchange of TDP-43 between cell somata and the presence of TDP-43 oligomers in microvesicles/exosomes and show that microvesicular TDP-43 is preferentially taken up by recipient cells where it exerts higher toxicity than free TDP-43. (
  • A fundamental shortcoming that hampers progress is the lack of animal models showing aggregation of TDP-43 without overexpression. (
  • Lilian Lin, a PhD student in Dr. Janice Robertson's Lab at the University of Toronto believes that the loss of the ability of the C9ORF72 gene to function properly and the aggregation of TDP-43 may be related events. (
  • However, how ALS-linked mutations in TDP-43 and FUS/TLS contribute to cellular toxicity is not understood. (
  • This work provides a mechanistic framework for investigating the toxicity of TDP-43 aggregation relevant to human disease and establishes a manipulable, high-throughput model for discovering potential therapeutic strategies. (
  • We have used yeast and in vitro biochemistry (in collaboration with Jim Shorter at PENN) to analyze the effects of ALS-linked TDP-43 mutations on aggregation and toxicity (Johnson et al. (
  • We are currently analyzing hits from recent high-throughput screens that identified potent modifiers of TDP-43 toxicity. (
  • 1. The genes and pathways that are able to modify TDP-43 toxicity in yeast are now good candidates for evaluation as genetic contributors to ALS and related disorders in humans (e.g., see ataxin 2 below). (
  • The authors also discovered that a region of the protein that has previously been found to be necessary for toxicity promotes its association with membranes, which may increase aggregation propensity. (
  • In this study we made no assumptions as to how TDP-43 injures cells," said Farese, "but instead screened the whole yeast genome to find genes that might prevent the toxicity. (
  • Three genes were identified that suppress TDP-43 toxicity, including shaggy /GSK3 , a known modifier of neurodegeneration. (
  • 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. (
  • The mechanism of that toxicity hasn't yet been found. (
  • Taken together, abnormal stability of mutant TDP-43 and its enhanced binding to normal FUS/TLS imply a convergence of pathogenic pathways from mutant TDP-43 and FUS/TLS in ALS. (
  • Researchers funded by The ALS Association, through donations from the ALS Ice Bucket Challenge, discovered new evidence on the role that mutant TDP-43 plays in development and progression of the disease. (
  • The researchers showed - by creating lariats with a binding site for a fluorescent tracking protein - that the mutant TDP-43 binds to these excess lariats rather than clumping. (
  • So decreasing the amount of DBR1 appears to rescue cells that die from the effects of mutant TDP-43. (
  • So in ALS, the accumulated lariats may serve as a decoy for the mutant TDP-43 protein, preventing it from binding to and interfering with more essential RNAs. (
  • 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. (
  • More recently, TDP-43 proteinopathy has been reported in dementia pugilistica or chronic traumatic encephalopathy caused by repetitive traumatic brain injury (TBI). (
  • 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. (
  • 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. (
  • show that the main culprit of proteinopathy, TDP-43, acts as a splicing suppressor of nonconserved cryptic exons. (
  • Because brains of ALS-FTD cases showed evidence of missplicing of cryptic exons, failure in these regions may underlie TDP-43 proteinopathy. (
  • However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. (
  • Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy. (
  • 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 ). (
  • 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. (
  • 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. (
  • Amador-Ortiz C, Lin WL, Ahmed Z et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. (
  • Arai T, Mackenzie IR, Hasegawa M et al (2009) Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies. (
  • TDP-43 also is tied to minor neurodegenerative disorders and, in a recent discovery, is present in many Alzheimer's disease patients, as well. (
  • 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. (
  • It also is found in 80 percent of chronic traumatic encephalopathy and 60 percent of Alzheimer's disease cases. (
  • Noting the trend in research implicating TDP-43 as a possible Alzheimer's mimic, a group of experts convened a workshop to provide a starting point for further research that will advance our understanding of another contributor to late life brain changes," Silverberg explained. (
  • Although these ALS associated genes, including RNA-binding protein (TDP-43), autophagy adaptor (UBQLN2), and a possible C9ORF72, have vastly different cellular functions in the typical clinical phenotype, mutations of these genes can all result in ALS. (
  • The authors of two papers, posted online February 27 by Nature Neuroscience, used a technique called crosslinking and immunoprecipitation (CLIP) to identify thousands of potential TDP-43 targets, among which hundreds of genes rely on the protein for splicing. (
  • The TDP-43 protein was found to target over one-third of the genes in modeled mouse brains. (
  • 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. (
  • Hammell's study interrogated the links between TDP-43 and retrotransposons, which are also called jumping genes for their ability to move from one location in a genome to another. (
  • This area was of interest to the research teams as TDP-43 is one protein that is able to keep jumping genes silent, and were found in elevated levels in some patients with ALS. (
  • 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 ). (
  • They kept finding mutations in the same five genes. (
  • In addition, we discuss the value and limitations of the different models and conclude that it remains a challenge to find more and better rodent models based on mutations in new genes causing ALS. (
  • These variations were found in candidate genes or through genome wide association studies [ 2 ]. (
  • The team found that not only were certain transposons not inhibited and triggered a storm of the jumping genes, but one fly transposon called ' gypsy ' appeared to be the lead culprit. (
  • 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. (
  • Mutations in the genes that cause MND are also found in some people who have sporadic MND. (
  • Researchers continue in their quest to find the mutations in other genes that cause familial MND in the 35% of familial MND families in which the genetic cause has yet to be identified. (
  • It is now possible to test for the presence of mutations in the SOD1, TDP43, FUS and C9ORF72 genes in a person diagnosed with familial MND. (
  • 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. (
  • After over 3,000 breeding experiments Dr Sreedharan found mutations in three 'good' genes that delay motor neurone death. (
  • If we can replicate the effects of these three 'good' genes, then it may be a step towards developing therapies against the damaging effects of TDP-43. (
  • These findings suggest that mutant SOD1 could affect the solubility/insolubility of TDP-43 through physical interactions and the resulting pathological modifications of TDP-43 may be involved in motor neuron death in SOD1 fALS. (
  • Conclusions: These results indicate that similar to SOD1 transgenic animals, local complement activation and increased Q331K expression of C5aR1 may contribute to motor neuron death and neuromuscular junction denervation in the TDP-43 mouse ALS model. (
  • The antibodies also clung to protein deposits in motor neuron samples from ALS patients, indicating that TDP-43 was present there, too. (
  • The evidence, a unique pattern of protein deposits, was found during autopsy studies of brains from 12 professional athletes who had played violent contact sports -- including three athletes diagnosed with motor neuron diseases before their deaths -- according to Ann C. McKee, MD, of Boston University, and colleagues. (
  • 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. (
  • 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). (
  • 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. (
  • It is still unclear, based on these results, what leads to motor neuron death in ALS due to TDP-43 mutation. (
  • Anti-TDP-43 immunohistochemistry and the recent development of novel tools, such as phosphorylation-specific TDP-43 antibodies, have increased our knowledge about the spectrum of pathological changes associated with FTLD-U and ALS and moreover, facilitated the neuropathological routine diagnosis of these conditions. (
  • This review summarizes the recent advances in our understanding on the molecular neuropathology and pathobiology of TDP-43 in FTLD and ALS. (
  • They noticed that TDP-43 in FTLD samples was more likely to bind to small, noncoding RNAs, including small nucleolar (sno)RNAs, small nuclear (sn)RNAs, and ribosomal and telomeric RNAs. (
  • When they examined their data quantitatively, the MRC scientists found that TDP binding to many transcripts was up- or downregulated in the FTLD samples relative to control tissue. (
  • TDP-43 binding to neurexin 3 mRNA dropped in FTLD tissue compared to normal. (
  • In FTLD tissue, two noncoding RNAs-nuclear paraspeckle assembly transcript 1 (NEAT1) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)-bound more TDP-43. (
  • Subjects were recruited from a consecutive series of patients with a primary neuropathologic diagnosis of FTLD-TDP and antemortem MRI. (
  • Twenty-eight patients met entry criteria: 9 with type 1, 5 with type 2, and 10 with type 3 FTLD-TDP. (
  • FTLD-TDP subtypes have distinct clinical and neuroimaging features, highlighting the relevance of FTLD-TDP subtyping to clinicopathologic correlation. (
  • The majority of FTLD-TDP cases are due to loss of function mutations in the gene encoding progranulin, a secreted growth factor. (
  • The present study set out to assess this and demonstrates that distinct TDP-43 inclusion morphologies exist in the anterior cingulate cortex, but not the motor cortex of FTLD and FTLD-ALS. (
  • All cases with a pathological diagnosis of FTLD-TDP and/or ALS-TDP were selected from a neuropathological series collected by the Sydney Brain Bank through regional brain donor programs in Sydney, Australia. (
  • Analysis of RNA binding by TDP-43 in brains from subjects with FTLD revealed that the greatest increases in binding were to the MALAT1 and NEAT1 noncoding RNAs. (
  • 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. (
  • Aggregation of the protein TDP-43 is a hallmark of a pathological process that leads to dementia called frontotemporal lobar degeneration (FTLD). (
  • Using a high-throughput sequencing approach combined with cross-linking immunoprecipitation (HITS-CLIP), direct targets of Tdp-43 have been identified ( 18 , 19 ). (
  • The mRNA targets of TDP-43 in the human brain and its role in RNA processing are largely unknown. (
  • Reduction of TDP-43 in cell culture leads to down-regulation of cyclin-dependent kinase 6 and histone deacetylase 6, further supporting TDP-43's role in regulating gene expression ( 17 , 18 ). (
  • TDP-43 oligomers have been postulated to be released and subsequently nucleate TDP-43 oligomerization in recipient cells, which might be the molecular correlate of the systematic symptom spreading observed during ALS progression. (
  • however, the role played by TDP-43 in disease onset and progression is still unclear. (
  • This important work sheds light on novel aspects of TDP-43 biology and provides valuable tools to gain insight into early stages of ALS disease progression and could lead to the development of new therapies. (
  • The mis-regulation of the mutated protein is central to disease pathways of ALS, but how these mutations cause ALS is largely unknown: both the loss of TDP-43's function and the gain of its function has been connected to disease development and progression. (
  • WT Q331K Methods: Non-transgenic, TDP-43 and TDP-43 mice were examined at three different ages of disease progression. (
  • New understandings about the relationship between hnRNP A1 and TDP-43 may lead to the development of new therapies and a biomarker to measure disease progression or the effectiveness of new treatments in clinical trials in the future. (
  • Before we can find a way to halt or slow ALS disease progression, or prevent it from occurring, we need to understand where we may be able to intervene in the process," said Lin. (
  • The amount of TDP-43 positive cell significantly increased at the onset and progression stages of ALS following with the increase of neuron death in spinal cord, particularly in the ventral horn of cervical segment at the progression stage. (
  • 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 ]. (
  • 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. (
  • To answer this question, they created a mammalian neuroblastoma cell line with an inducible system for making a mutant version of TDP-43, TDP-43 Gln331Lys, found commonly in ALS patients. (
  • TDP-35 is a novel version of TDP-43 developed in Dr. Robertson's lab that is an excellent model for studying the behaviour of TDP-43. (
  • Here, they used a variety of spectroscopic and microscopic techniques to characterize in detail the structure of the C-terminal prion-like domain of TDP-43, and how the protein forms dynamic oligomers through interactions of the domain on separate protein molecules or by interacting with nucleic acid. (
  • Lim L, Wei Y, Lu Y, Song J (2016) ALS-Causing Mutations Significantly Perturb the Self-Assembly and Interaction with Nucleic Acid of the Intrinsically Disordered Prion-Like Domain of TDP-43. (
  • Expression inDrosophila TDP-43 knockout models of a chimeric repressor, comprised of the RNA recognition domain of TDP-43 fused to an unrelated splicing repressor, RAVER1, attenuated motor deficits and extended lifespan. (
  • Masao Yahara, Akira Kitamura and Masataka Kinjo from Hokkaido University in Japan decided to investigate this relationship at a molecular level in order to understand exactly how the depletion of TDP-43 leads to cell death and ALS. (
  • By analyzing the prerequisites for SG recruitment of TDP-43 and FUS, I demonstrate that cytosolic mislocalization of TDP-43 and FUS is required for their localization in SGs. (
  • Now, in Dr. Robertson's lab at the University of Toronto, Lin is looking forward to finding out if there is a relationship between C9ORF72 deficiency and the mislocalization of TDP-43 by working with mouse models. (
  • Note that when a researcher deletes out the full TDP-43 gene, called TDP-43 null, the mice do not live beyond embryonic day six. (
  • This study therefore aimed to determine the expression of several key complement components and regulators in the Q331K lumbar spinal cord and tibialis anterior muscle of TDP-43 mice during different disease ages. (
  • Results: Altered levels of several major complement factors, including C5a, in the spinal cord and tibialis anterior Q331K muscle of TDP-43 mice were observed as disease progressed, suggesting overall increased complement Q331K activation in TDP-43 mice. (
  • TDP-43 mice also have moderate overexpres- tients, as well as in transgenic SOD1 animal models of sion levels in total TDP-43, with a 2.5-fold increase in total ALS . (
  • The findings demonstrate that the co-aggregation of DISC1 caused the abnormalities in the model mice, suggesting that the co-aggregation of DISC1 with TDP-43 may disrupt cellular function and trigger psychiatric manifestations. (
  • Then she will introduce TDP-35 protein into the brains of the mice. (
  • We wanted to find out if we could protect these mice from the consequences of TDP-43 by lowering the amount of ataxin 2," said Gitler. (
  • She found that with half the ataxin 2, the ALS-like mice survived much longer. (