TDP-43 and Mitochondrial Dysfunction in ALS
TDP-43 and Mitochondrial Dysfunction in ALS
批准号:
8799706
负责人:
Xinglong Wang
金额:
$34.67万
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-09-30 至 2019-07-31
关键词:
AddressAffectAmyotrophic Lateral SclerosisBindingBioenergeticsBrain StemCell LineCell NucleusCell-Free SystemCellsComplexCytoplasmDNA-Binding ProteinsDataDiseaseElectron TransportEssential Amino AcidsFrontotemporal Lobar DegenerationsGenesImpairmentIn VitroInvestigationLeadMediatingMembraneMessenger RNAMitochondriaMitochondrial MatrixMitochondrial ProteinsMolecularMotorMotor Neuron DiseaseMotor NeuronsMutationNerve DegenerationNeurodegenerative DisordersNeuronal DysfunctionNeuronsNuclearOrganellesOutcomePathogenesisPathologyPathway interactionsPhysiologicalPilot ProjectsPlayPost-Translational Protein ProcessingPrimary Cell CulturesProtein ImportProteinsRegulationRoleSiteSpinal CordTestingTherapeutic InterventionTimeToxic effectTransgenic MiceTranslationsbaseeffective therapyin vivoinsightmitochondrial dysfunctionmitochondrial genomemitochondrial messenger RNAmutantnew therapeutic targetnovelprogressive neurodegenerationprotein TDP-43protein expressionpublic health relevance
中文摘要
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英文摘要
DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is the most common of the five motor neuron diseases characterized by progressive neurodegeneration of motor neurons in the brain stem and spinal cord. Currently, there is no cure or effective treatment for ALS. The cause of disease is unknown in the majority of ALS cases. Less than 10% of ALS cases are familial, involving mutations in several genes such as SOD1 and TARDBP. The protein encoded by TARDBP, i.e. TAR DNA-binding protein 43 (TDP-43), was identified as a major component of the histopathological hallmark, i.e., neuronal ubiquitinated inclusions, of degenerating neurons in most forms of ALS and increasing evidence suggests a critical role of TDP-43 in diverse neurodegenerative diseases including ALS and frontotemporal lobar degeneration (FTLD). Unfortunately, how TDP-43 mutant causes neurodegeneration is poorly understood. Interestingly, in our preliminary studies, we also observed significant impairment of mitochondrial bioenergetics in motor neuronal cell lines expressing mutant TDP-43. As mitochondrial dysfunction plays a prominent role in ALS, further more detailed studies should be performed to assess the effect of mutant TDP-43 on mitochondrial function in primary motor neurons in vitro and in vivo, and explore potential underlying mechanisms by which mutant TDP- 43 cause mitochondrial dysfunction. TDP-43 translocates from the nucleus to cytoplasm in of ALS and frontotemporal lobar degeneration (FTLD-U). Unfortunately, few attempt has been taken to investigate its subcellular organelle target(s). Excitingly, our pilot studies found that TDP-43 could be present in the matrix of mitochondria. And, more importantly, TDP-43 interacts with a matrix facing protein critical for mitochondrial electron transport chain, and binds mitochondrial genome encoded mRNA, indicating a direct role of TDP-43 in regulating mitochondrial function. All these exciting finding strongly suggest that TDP-43 may impair mitochondrial function through its specific localization in mitochondria which adversely affects neuronal functions in ALS. Thus, it is important to investigate how TDP-43 is taken up by mitochondria and test whether TDP-43 mitochondrial localization is required for its toxicity on mitochondria and neurons. Our proposed study will be the first systematic and mechanistic study of TDP-43 mitochondrial import as well as TDP-43 induced mitochondrial dysfunction. Our proposed studies will reveal a novel role of TDP-43 in the regulation of mitochondrial function and likely provide novel therapeutic targets for ALS.
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会议论文
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海外基金