Journal
NATURE NEUROSCIENCE
Volume 21, Issue 2, Pages 228-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41593-017-0047-3
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Funding
- ALS Association [17-IIP-353, 16-IIP-278]
- Emory Medicine Catalyst Funding Program
- Muscular Dystrophy Association [MDA348086]
- NIH [K08-NS087121, P30-NS055077, AG025688, R01-NS091299, R35-NS097261, R01-NS085207, R01NS091749, R01-NS093362, R01-AG053960]
- The Bluefield Project to Cure FTD
- Alzheimers Drug Discovery Foundation
- Alzheimers Association (ALZ)
- Alzheimers Research UK (ARUK)
- The Michael J. Fox Foundation for Parkinsons Research (MJFF)
- Weston Brain Institute Biomarkers Across Neurodegenerative Diseases Grant [11060]
- UBRP
- UA Provosts Office
- ARCS Fellowship Roche Foundation Award
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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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