TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD
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Author
Chou, Ching-ChiehZhang, Yi
Umoh, Mfon E.
Vaughan, Spencer W.
Lorenzini, Ileana
Liu, Feilin
Sayegh, Melissa
Donlin-Asp, Paul G.
Chen, Yu Han
Duong, Duc M.
Seyfried, Nicholas T.
Powers, Maureen A.
Kukar, Thomas
Hales, Chadwick M.
Gearing, Marla
Cairns, Nigel J.
Boylan, Kevin B.
Dickson, Dennis W.
Rademakers, Rosa
Zhang, Yong-Jie
Petrucelli, Leonard
Sattler, Rita
Zarnescu, Daniela C.

Glass, Jonathan D.
Rossoll, Wilfried
Affiliation
Univ Arizona, Dept Mol & Cellular BiolIssue Date
2018-02
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NATURE PUBLISHING GROUPCitation
Chou, C. C., Zhang, Y., Umoh, M. E., Vaughan, S. W., Lorenzini, I., Liu, F., ... & Seyfried, N. T. (2018). TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nature neuroscience, 21, pp 228–239, https://doi.org/10.1038/s41593-017-0047-3Journal
NATURE NEUROSCIENCERights
Copyright © 2018, Springer Nature.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
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.Note
6 month embargo; published online: 08 January 2018ISSN
1097-62561546-1726
PubMed ID
29311743Version
Final accepted manuscriptSponsors
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 AwardAdditional Links
http://www.nature.com/articles/s41593-017-0047-3ae974a485f413a2113503eed53cd6c53
10.1038/s41593-017-0047-3
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