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    TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD

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    Thumbnail
    Name:
    72404_3_merged_1512399616.pdf
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    PDF
    Description:
    Final Accepted Manuscript
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    Author
    Chou, Ching-Chieh
    Zhang, 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. cc
    Glass, Jonathan D.
    Rossoll, Wilfried
    Show allShow less
    Affiliation
    Univ Arizona, Dept Mol & Cellular Biol
    Issue Date
    2018-02
    
    Metadata
    Show full item record
    Publisher
    NATURE PUBLISHING GROUP
    Citation
    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/s41593-017-0047-3
    Journal
    NATURE NEUROSCIENCE
    Rights
    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 2018
    ISSN
    1097-6256
    1546-1726
    PubMed ID
    29311743
    DOI
    10.1038/s41593-017-0047-3
    Version
    Final accepted manuscript
    Sponsors
    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
    Additional Links
    http://www.nature.com/articles/s41593-017-0047-3
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41593-017-0047-3
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