BIROn - Birkbeck Institutional Research Online

    Human Hsp70 Disaggregase reverses Parkinson’s-linked α-Synuclein Amyloid Fibrils

    Gao, X. and Carroni, Marta and Nussbaum-Krammer, C. and Mogk, A. and Nillegoda, N.B. and Szlachcic, A. and Guilbride, D.L. and Saibil, Helen R. and Mayer, M.P. and Bukau, B. (2015) Human Hsp70 Disaggregase reverses Parkinson’s-linked α-Synuclein Amyloid Fibrils. Molecular Cell 59 (5), pp. 781-793. ISSN 1097-2765.

    [img]
    Preview
    Text
    12891.pdf - Author's Accepted Manuscript

    Download (3MB) | Preview

    Abstract

    Intracellular amyloid fibrils linked to neurodegenerative disease typically accumulate in an age-related manner, suggesting inherent cellular capacity for counteracting amyloid formation in early life. Metazoan molecular chaperones assist native folding and block polymerization of amyloidogenic proteins, preempting amyloid fibril formation. Chaperone capacity for amyloid disassembly, however, is unclear. Here, we show that a specific combination of human Hsp70 disaggregase-associated chaperone components efficiently disassembles α-synuclein amyloid fibrils characteristic of Parkinson’s disease in vitro. Specifically, the Hsc70 chaperone, the class B J-protein DNAJB1, and an Hsp110 family nucleotide exchange factor (NEF) provide ATP-dependent activity that disassembles amyloids within minutes via combined fibril fragmentation and depolymerization. This ultimately generates non-toxic α-synuclein monomers. Concerted, rapid interaction cycles of all three chaperone components with fibrils generate the power stroke required for disassembly. This identifies a powerful human Hsp70 disaggregase activity that efficiently disassembles amyloid fibrils and points to crucial yet undefined biology underlying amyloid-based diseases.

    Metadata

    Item Type: Article
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 26 Aug 2015 15:41
    Last Modified: 28 Jul 2019 23:10
    URI: http://eprints.bbk.ac.uk/id/eprint/12891

    Statistics

    Downloads
    Activity Overview
    147Downloads
    617Hits

    Additional statistics are available via IRStats2.

    Archive Staff Only (login required)

    Edit/View Item Edit/View Item