title: Human Hsp70 Disaggregase Reverses Parkinson's-Linked α-Synuclein Amyloid Fibrils.
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.
authors: Center for Molecular Biology of the University of Heidelberg (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors: Xuechao
authors: X
authors: Gao
authors: Department of Crystallography, Institute for Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, UK.
authors: Marta
authors: M
authors: Carroni
authors: Center for Molecular Biology of the University of Heidelberg (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors: Carmen
authors: C
authors: Nussbaum-Krammer
authors: Center for Molecular Biology of the University of Heidelberg (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors: Axel
authors: A
authors: Mogk
authors: Center for Molecular Biology of the University of Heidelberg (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors: Nadinath B
authors: NB
authors: Nillegoda
authors: Center for Molecular Biology of the University of Heidelberg (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors: Anna
authors: A
authors: Szlachcic
authors: ZMBH, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors: D Lys
authors: DL
authors: Guilbride
authors: Department of Crystallography, Institute for Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, UK.
authors: Helen R
authors: HR
authors: Saibil
authors: ZMBH, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors: Matthias P
authors: MP
authors: Mayer
authors: Center for Molecular Biology of the University of Heidelberg (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany. Electronic address: bukau@zmbh.uni-heidelberg.de.
authors: Bernd
authors: B
authors: Bukau
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D055032:Electron Microscope Tomography; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D050957:HSP110 Heat-Shock Proteins / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D018832:Molecular Chaperones / Q000378:metabolism; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism*; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D055503:Protein Multimerization; D012995:Solubility; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism
chemical_list: D000682:Amyloid; C494647:DNAJB1 protein, human; D050883:HSC70 Heat-Shock Proteins; D050957:HSP110 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D018832:Molecular Chaperones; D066329:Protein Aggregates; D051844:alpha-Synuclein