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 3.1.25.2.Rabbits: The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.Electrophysiologic Techniques, Cardiac: Methods to induce and measure electrical activities at specific sites in the heart to diagnose and treat problems with the heart's electrical system.Pentamidine: Antiprotozoal agent effective in trypanosomiasis, leishmaniasis, and some fungal infections; used in treatment of PNEUMOCYSTIS pneumonia in HIV-infected patients. It may cause diabetes mellitus, central nervous system damage, and other toxic effects.DNA-Binding Proteins: Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.DNA Adducts: The products of chemical reactions that result in the addition of extraneous chemical groups to DNA.Potassium Channels, Voltage-Gated: Potassium channel whose permeability to ions is extremely sensitive to the transmembrane potential difference. The opening of these channels is induced by the membrane depolarization of the ACTION POTENTIAL.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Quinidine: An optical isomer of quinine, extracted from the bark of the CHINCHONA tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular ACTION POTENTIALS, and decreases automaticity. Quinidine also blocks muscarinic and alpha-adrenergic neurotransmission.Furans: Compounds with a 5-membered ring of four carbons and an oxygen. They are aromatic heterocycles. The reduced form is tetrahydrofuran.DNA, Single-Stranded: A single chain of deoxyribonucleotides that occurs in some bacteria and viruses. It usually exists as a covalently closed circle.Transketolase: An enzyme of the transferase class that catalyzes the conversion of sedoheptulose 7-phosphate and D-glyceraldehyde 3-phosphate to D-ribose 5-phosphate and D-xylulose 5-phosphate in the PENTOSE PHOSPHATE PATHWAY. (Dorland, 27th ed) EC 2.2.1.1.Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.Patents as Topic: Exclusive legal rights or privileges applied to inventions, plants, etc.Tetracyclines: Closely congeneric derivatives of the polycyclic naphthacenecarboxamide. (Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed, p1117)Biomimetics: An interdisciplinary field in materials science, ENGINEERING, and BIOLOGY, studying the use of biological principles for synthesis or fabrication of BIOMIMETIC MATERIALS.Heart Rate: The number of times the HEART VENTRICLES contract per unit of time, usually per minute.Quaternary Ammonium Compounds: Derivatives of ammonium compounds, NH4+ Y-, in which all four of the hydrogens bonded to nitrogen have been replaced with hydrocarbyl groups. These are distinguished from IMINES which are RN=CR2.DNA Breaks, Double-Stranded: Interruptions in the sugar-phosphate backbone of DNA, across both strands adjacently.Polyneuropathies: Diseases of multiple peripheral nerves simultaneously. Polyneuropathies usually are characterized by symmetrical, bilateral distal motor and sensory impairment with a graded increase in severity distally. The pathological processes affecting peripheral nerves include degeneration of the axon, myelin or both. The various forms of polyneuropathy are categorized by the type of nerve affected (e.g., sensory, motor, or autonomic), by the distribution of nerve injury (e.g., distal vs. proximal), by nerve component primarily affected (e.g., demyelinating vs. axonal), by etiology, or by pattern of inheritance.Alkylation: The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group.Disease Models, Animal: Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.Cell Extracts: Preparations of cell constituents or subcellular materials, isolates, or substances.NAV1.5 Voltage-Gated Sodium Channel: A voltage-gated sodium channel subtype that mediates the sodium ion PERMEABILITY of CARDIOMYOCYTES. Defects in the SCN5A gene, which codes for the alpha subunit of this sodium channel, are associated with a variety of CARDIAC DISEASES that result from loss of sodium channel function.Amiodarone: An antianginal and class III antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting POTASSIUM CHANNELS and VOLTAGE-GATED SODIUM CHANNELS. There is a resulting decrease in heart rate and in vascular resistance.Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.DNA Ligases: Poly(deoxyribonucleotide):poly(deoxyribonucleotide)ligases. Enzymes that catalyze the joining of preformed deoxyribonucleotides in phosphodiester linkage during genetic processes during repair of a single-stranded break in duplex DNA. The class includes both EC 6.5.1.1 (ATP) and EC 6.5.1.2 (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.
  • Whereas a pathological link to neurodegenerative disorders has been established, the cellular and physiological functions of TDP-43 remain unknown. (nih.gov)
  • The normal functions of TDP-43 are not established, although it has been proposed that TDP-43 is involved in transcription repression ( 12 , 13 ) and splicing regulation ( 14 - 16 ). (pnas.org)
  • A detailed description of the determinants for cellular localization has yet to emerge, including information on how the known functions of TDP-43 and cellular targeting affect each other. (biologists.org)
  • And, what are the really important functions of TDP-43 that happen in cells, functions that would cause the degeneration of neurons without them? (slu.edu)
  • Interestingly, it was determined that the glutamate transporter EAAT1 mediates the regulatory functions of TDP-43 in the glia, and genetic or pharmacological compensations of EAAT1 activity were demonstrated to be sufficient to modulate glutamate receptor clustering and locomotive behaviors in flies. (sdbonline.org)
  • The data uncovers autonomous and non-autonomous functions of TDP-43 in glia and suggests new experimentally based therapeutic strategies in ALS. (sdbonline.org)
  • But, he cautions, first "we need to learn more about normal functions of TDP-43. (asbmb.org)
  • Both of these identified genes, DDX58 and MTHFSD, are RNA-binding proteins, and we show that TDP-43 binds to their respective mRNAs and we identify MTHFSD as a novel component of stress granules. (nih.gov)
  • Under conditions of stress, TDP-43 translocates from the nucleus to the cytoplasm, competes with FOXO transcription factors for binding to 14-3-3 proteins, and releases FOXO for nuclear translocation and activation. (prolekarniky.cz)
  • Tdp-43 is a protein that regulates the process of making proteins from genes. (eurekalert.org)
  • Using isogenic cell lines expressing wild-type or ALS-linked TDP-43 mutants and fibroblasts from a human patient, pulse-chase radiolabeling of newly synthesized proteins is used to determine, surprisingly, that ALS-linked TDP-43 mutant polypeptides are more stable than wild-type TDP-43. (pnas.org)
  • Tandem-affinity purification and quantitative mass spectrometry are used to identify TDP-43 complexes not only with heterogeneous nuclear ribonucleoproteins family proteins, as expected, but also with components of Drosha microprocessor complexes, consistent with roles for TDP-43 in both mRNA processing and microRNA biogenesis. (pnas.org)
  • In addition to a nuclear function, TDP-43 also colocalizes with fragile X mental-retardation protein (FMRP) and Staufen proteins in the neurites of primary neurons, which suggests a role in RNA transport and localization ( 20 ). (pnas.org)
  • When TDP-43 was depleted in cells, a set of nonconserved cryptic exons spliced into target RNAs, leading to down-regulation of corresponding proteins critical for cellular function. (sciencemag.org)
  • The TDP-43 protein attaches (binds) to DNA and regulates an activity called transcription, which is the first step in the production of proteins from genes. (medlineplus.gov)
  • The TDP-43 protein is involved in processing molecules called messenger RNA (mRNA), which serve as the genetic blueprints for making proteins. (medlineplus.gov)
  • By cutting and rearranging mRNA molecules in different ways, the TDP-43 protein controls the production of different versions of certain proteins. (medlineplus.gov)
  • Many of the proteins whose production is influenced by the TDP-43 protein are involved in nervous system and organ development. (medlineplus.gov)
  • For TDP-43 and other RNA binding proteins, very little is known about when they will form, how many will form and how big they are. (slu.edu)
  • The SLU team decided to see if phosphorylation - one of the most common ways that proteins are regulated - may be responsible for managing the activity, location and how tightly the protein binds. (slu.edu)
  • The research team found a new role of three proteins (PTK2, TBK1, SQSTM1) which can inhibit neuronal degeneration by TDP-43 and demonstrated for the first time that their interaction can alleviate neurodegeneration by strengthening "autophagy lysosome pathway (ALP),*" which consists of another protein quality control system in case of damage to the UPS. (innovations-report.com)
  • In a search for proteins that may affect microglia/neuron immune crosstalk in aging brain, we focused our study on transactive response (TAR) DNA binding protein 43 (TDP-43). (biomedcentral.com)
  • Unlike people who have Alzheimer's disease, people with limbic-predominant age-related TDP-43 encephalopathy (LATE) don't accumulate beta-amyloid or tau proteins in their brains. (newscientist.com)
  • Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. (rupress.org)
  • TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. (rupress.org)
  • Stress granule recruitment and deposition of proteins of the FET family and TDP-43 in ALS and FTD. (uni-muenchen.de)
  • TDP-43 pathology occurs in distinct brain regions, involves disparate brain networks, and features accumulation of misfolded proteins in various cell types and in different neuroanatomical regions. (springer.com)
  • Together, our results demonstrate an overlapping role for SCYL1 and SCYL3 in vivo and highlight the importance the SCYL family of proteins in regulating neuronal function and survival. (jneurosci.org)
  • Background: TAZ is a transcriptional co-activator with a PDZ-binding motif that is regulated by its interaction with 14-3-3 proteins (1). (cellsignal.com)
  • In general, TDP-43 acts like a chaperone for RNA in a cell, binding to it, guiding its processing, transporting it to where it needs to go and regulating it, so that other proteins can be expressed properly. (brown.edu)
  • Further explain that in 10 pro athletes with a history of repeated head trauma, pathologists discovered extensive brain deposits of a DNA-binding protein called TDP-43 and neurofibrillary tau protein -- but the tau proteins found in three motor neuron disease cases were different from those seen in sporadic ALS patients. (medpagetoday.com)
  • The deposits of the TDP-43 and tau proteins, found post-mortem in numerous regions of 10 of the pro athletes' brains provided "the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease," the researchers commented. (medpagetoday.com)
  • Additionally we are shipping Granulin Kits (120) and Granulin Proteins (43) and many more products for this protein. (antibodies-online.com)
  • TDP-43 is one of many proteins that binds to RNA, which is responsible for transmitting genetic information and translating it into a concise recipe for a given protein, for example, part of a growing neuron. (harvard.edu)
  • The two proteins that contribute to the disease - FUS/TLS and TDP-43 - bind to ribonucleic acid (RNA), intermediate molecules that translate genetic information from DNA to proteins. (ucsd.edu)
  • TDP-43 is a known protein widely expressed throughout the body, with multiple functions, including regulating transcription of the genetic code and as scaffolding for nuclear and motor neuron proteins. (medicalxpress.com)
  • The identification of misfolded TDP-43 proteins in neurons of brain tissue (brown structures indicated by arrows) was a criterion for entry into this genome-wide study. (medicalxpress.com)
  • How TDP-43, GRN, and TMEM106B proteins might normally interact in brain cells and be disrupted in FTLD remains to be deciphered. (medicalxpress.com)
  • Senior Researcher Yun Ha Jeong from the Korea Brain Research Institute said, "This study suggests that Tdp-43 proteinopathy and specific cryptic exons are involved in the process of degenerative brain and muscle disorders in a unique way. (eurekalert.org)
  • show that the main culprit of proteinopathy, TDP-43, acts as a splicing suppressor of nonconserved cryptic exons. (sciencemag.org)
  • Because brains of ALS-FTD cases showed evidence of missplicing of cryptic exons, failure in these regions may underlie TDP-43 proteinopathy. (sciencemag.org)
  • However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. (sciencemag.org)
  • Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy. (sciencemag.org)
  • More recently, TDP-43 proteinopathy has been reported in dementia pugilistica or chronic traumatic encephalopathy caused by repetitive traumatic brain injury (TBI). (springer.com)
  • While a single TBI has been linked to the development of Alzheimer's disease and an increased frequency of neurofibrillary tangles, TDP-43 proteinopathy has not been examined with survival following a single TBI. (springer.com)
  • Moreover, while single TBI can induce multiple long-term neurodegenerative changes, the absence of TDP-43 proteinopathy may indicate a fundamental difference in the processes induced following single TBI from those of repetitive TBI. (springer.com)
  • Finally, we attempt to integrate these findings into the emerging picture of TDP-43 proteinopathy, and to highlight key issues for future therapy and research. (springer.com)
  • In this review, we summarize recent advances in the neuropathology, genetics and animal models of TDP-43 proteinopathy, and discuss their relationship to clinical phenotypes, their place in the emerging picture of TDP-43 proteinopathy, and their relevance to the development of therapeutic interventions. (springer.com)
  • In contrast to RBPs that regulate splicing of conserved exons, we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity. (sciencemag.org)
  • In this study, we show that TDP-43 is a nuclear protein with persistent high-level expression during embryonic development and with progressively decreased protein levels during postnatal development. (nih.gov)
  • 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. (kcl.ac.uk)
  • Using a high-throughput sequencing approach combined with cross-linking immunoprecipitation (HITS-CLIP), direct targets of Tdp-43 have been identified ( 18 , 19 ). (sciencemag.org)
  • In 2011, this team of UC San Diego scientists discovered that more than one-third of the genes in the brains of mice are direct targets of TDP-43, affecting the functions of these genes. (ucsd.edu)
  • Pathological TDP-43 is abnormally ubiquitinated, hyperphosphorylated, and N-terminally cleaved to generate CTFs ( 4 , 5 ). (pnas.org)
  • Pathological modifications of TDP-43 include proteolytic fragmentation, phosphorylation, and ubiquitinylation. (medworm.com)
  • TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD. (wikipedia.org)
  • The discovery of TDP-43 as the pathological link between mechanisms of nervous system degeneration in both ALS and FTLD opened up new opportunities for drug discovery as well as biomarker development for these disorders," says Lee. (scienceblog.com)
  • 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. (pnas.org)
  • Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and, thus, plays an important role in the early phase of insulin secretion by pancreatic islets. (jci.org)
  • We also demonstrate that endogenous TDP-43 and FUS do not have overlapping functions in this cellular process as SG initiation and assembly occur normally in the absence of FUS. (molecularneurodegeneration.com)
  • Furthermore, we investigate the role of the functional TDP-43 domains in determining cellular targeting through a combination of immunofluorescence and biochemical fractionation methods. (biologists.org)
  • Our results provide insight into how the v-ATPase regulates mTORC1, and reveal a unique approach for enhancing cellular clearance based on covalent inhibition of lysosomal mTORC1 signaling. (nature.com)
  • Signal peptide peptidase-like 3 (SPPL3) is a type II membrane protein-selective sheddase that regulates cellular N-glycosylation. (uni-muenchen.de)
  • Chaperones display dynamic responses to exogenous and endogenous stressors and thus constitute a key component of the proteostasis network (PN), an intricately regulated network of quality control and repair pathways that cooperate to maintain cellular proteostasis. (biologists.org)
  • Cellular oxidation/reduction (redox) states regulate various aspects of cellular function and maintain homeostasis [ 1 ]. (hindawi.com)
  • TDP-43 is a multifunctional protein with many known cellular roles. (neurodegenerationresearch.eu)
  • VCP (p97 in mouse, TER94 in Drosophila melanogaster, and CDC48 in Saccharomyces cerevisiae) is a highly conserved AAA(+) (ATPases associated with multiple cellular activities) ATPase that regulates a wide array of cellular processes. (uzh.ch)
  • Our findings suggest that TDP-43 solubility and localization are particularly sensitive to disruptions that extend beyond the newly found nuclear localization signal and depend on a combination of factors that are closely connected to the functional properties of this protein. (biologists.org)
  • Dose-Dependent Motor Neuron Disease in TDP43 WT Mice. (pnas.org)
  • In particular, presence of TDP-43 affects the exon usage of the cystic fibrosis transmembrane regulator (CFTR), apolipoprotein A-II, and survival of motor neuron (SMN) transcripts ( 14 - 16 ). (pnas.org)
  • This study describes the generation and characterization of a new fly model of ALS-TDP with transgenic expression of the Drosophila ortholog of TDP-43, dTDP, in adult flies under the control of a temperature sensitive motor neuron-specific GAL4, thus bypassing the deleterious effect of dTDP during development. (sdbonline.org)
  • Once we had a connection between the TDP-43 and the loss of this other critical gene, STMN2 , we could see how a motor neuron might begin to fail in ALS," said Joseph Klim , postdoctoral fellow in the Harvard Department of Stem Cell and Regenerative Biology (SCRB). (harvard.edu)
  • These results indicate that TDP-43 is developmentally regulated and indispensible for early embryonic development. (nih.gov)
  • Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. (jci.org)
  • The mitochondrial localization of TDP-43 is dependent on its M1 motif, the deletion of which suppresses its mitochondrial accumulation. (padiracinnovation.org)
  • However, misfolded TDP-43 is very common in older adults, and the team behind the new guidelines say that roughly a quarter of people over the age of 85 have enough abnormal TDP-43 to affect their memory and thinking ability. (newscientist.com)
  • Moreover, the characteristic ≈25-kDa C-terminal fragments (CTFs) were also recovered from nuclear fractions and correlated with disease development and progression in WT TDP-43 mice. (pnas.org)
  • For example, the TDP-43 knockout mice die in early embryogenesis, making it difficult to tease out the physiological functions of the protein. (asbmb.org)
  • Further studies revealed that activation of TFEB induced by trehalose was responsible for the enhancement of autophagy and clearance of TDP-43 level. (springer.com)