Atypical TDP43 isoforrms driving neurodegeneration in FTD/ALS
非典型 TDP43 亚型导致 FTD/ALS 神经退行性变
基本信息
- 批准号:10534172
- 负责人:
- 金额:$ 39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:ALS patientsAddressAffectAlternative SplicingAmino AcidsAmyotrophic Lateral SclerosisAntibodiesAutomobile DrivingAutopsyBindingBrainC9ORF72CRISPR/Cas technologyCell DeathCell NucleusCharacteristicsClinicalCultured CellsCytoplasmDataDepositionDiseaseDisease modelDisparateExclusionFrontotemporal DementiaGenerationsGenome engineeringGoalsHomeostasisHumanHyperactivityIn VitroInduced MutationInduced pluripotent stem cell derived neuronsLabelLengthLinkMichiganModelingMutationNerve DegenerationNeuronsNuclearNuclear ExportNuclear ProteinPathogenesisPathologicPathologyPathway interactionsPatientsPlayPrevalenceProductionProtein IsoformsProteinsRNARNA SplicingRNA-Binding ProteinsReagentReporterRodentSpecificityStressTestingTherapeuticTimeTissuesToxic effectTranscriptUniversitiescohortdesignfrontotemporal lobar dementia amyotrophic lateral sclerosisin vivoinduced pluripotent stem celllocked nucleic acidmutantneuron lossneuroprotectionnovelnovel therapeuticsoverexpressionpreventprotein TDP-43stress granulestressortargeted treatmenttherapeutically effectivetherapy development
项目摘要
Cytosolic mislocalization of the RNA binding protein TDP43 and neuronal hyperexcitability are cardinal
features of TDP43-related frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Nuclear
exclusion and cytosolic deposition of TDP43 are found in over half of those with FTD, and nearly 95% of those
with ALS, but the origin of these changes remains unknown. Likewise, neuronal hyperexcitability is a
ubiquitous finding in FTD/ALS patients, in vivo and in vitro disease models, yet the cause and consequences of
this phenomenon are unclear. Our preliminary data show for the first time an intrinsic connection between
TDP43 deposition and neuronal hyperexcitabilty that may play a pivotal part in the neurodegeneration
observed in TDP43-related FTD/ALS. Elevated neuronal activity upregulates an uncommon TDP43 isoform
that lacks the canonical, low-complexity carboxy-terminus of the protein. Due to its active nuclear export and its
ability to bind full-length (fl)TDP43, This shortened (s)TDP43 isoform is actively exported from the nucleus,
accumulates in cytosolic aggregates, and sequestrates full-length (fl)TDP43, thereby recapitulating TDP43
pathology in FTD/ALS. Our central goal with this project is to determine the impact of sTDP43 in FTD/ALS
pathogenesis, with a long-term objective of defining novel and effective therapeutic strategies targeting TDP43
homeostasis. We will test the hypothesis that sTDP43 drives neurodegeneration in TDP43-related FTD/ALS by
three specific aims. First, we will take advantage of an sTDP43-specific antibody that we developed to
determine the prevalence and distribution of sTDP43 accumulation in a large cohort of sporadic and familial
FTD/ALS cases curated by the University of Michigan Brain Bank. We will also investigate the impact of
sTDP43 on RNA homeostasis, and determine the relationship between sTDP43, stress, and stress granules in
disease models. Lastly, we will assess the contribution of sTDP43 to neurodegeneration in rodent primary
neurons and human induced pluripotent stem cell-derived neurons from patients carrying FTD/ALS-associated
C9orf72 hexanucleotide expansion mutations. At the completion of these studies, we will have delineated a
unique disease mechanism leading to neurodegeneration in TDP43-related FTD/ALS, and highlighted potential
therapeutic approaches focusing on the abnormal activity-dependent production of toxic TDP43 isoforms.
胞质中RNA结合蛋白TDP43的错定位和神经元的高兴奋性是主要原因
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Sami Barmada其他文献
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{{ truncateString('Sami Barmada', 18)}}的其他基金
Spatiotemporal analysis of TDP-43 toxicity and endolysosomal turnover mechanisms
TDP-43毒性和内溶酶体周转机制的时空分析
- 批准号:
10626673 - 财政年份:2022
- 资助金额:
$ 39万 - 项目类别:
Atypical TDP43 isoforrms driving neurodegeneration in FTD/ALS
非典型 TDP43 亚型导致 FTD/ALS 神经退行性变
- 批准号:
10295762 - 财政年份:2019
- 资助金额:
$ 39万 - 项目类别:
Atypical TDP43 isoforrms driving neurodegeneration in FTD/ALS
非典型 TDP43 亚型导致 FTD/ALS 神经退行性变
- 批准号:
10057282 - 财政年份:2019
- 资助金额:
$ 39万 - 项目类别:
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减
- 批准号:
10619646 - 财政年份:2016
- 资助金额:
$ 39万 - 项目类别:
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减
- 批准号:
9973175 - 财政年份:2016
- 资助金额:
$ 39万 - 项目类别:
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减
- 批准号:
9324055 - 财政年份:2016
- 资助金额:
$ 39万 - 项目类别:
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减
- 批准号:
10206705 - 财政年份:2016
- 资助金额:
$ 39万 - 项目类别:
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减
- 批准号:
9750843 - 财政年份:2016
- 资助金额:
$ 39万 - 项目类别:
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减
- 批准号:
10435488 - 财政年份:2016
- 资助金额:
$ 39万 - 项目类别:
Elucidating the Mechanisms Underlying Mutant TDP43-induced Neurodegeneration
阐明突变 TDP43 诱导的神经变性的机制
- 批准号:
8725311 - 财政年份:2011
- 资助金额:
$ 39万 - 项目类别:
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