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Title
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TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD
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Author
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Abstract
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| The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD. |
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Language
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English
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Source (journal)
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Nature neuroscience. - London
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Publication
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London
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2018
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ISSN
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1097-6256
[Print]
1546-1726
[Online]
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DOI
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10.1038/S41593-017-0047-3
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Volume/pages
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21
:2
(2018)
, p. 228-239
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ISI
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000424269900014
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Full text (Publisher's DOI)
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