Human Hsp70 Disaggregase Reverses Parkinson’s-Linked α-Synuclein Amyloid Fibrils

Abstract

Summary 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.

Members of the Hsp70 Family Recognize Distinct Types of Sequences to Execute ER Quality Control

“…Alternatively, the aggregation we observed could in part be due to a concomitant release of BiP and Grp170 as a consequence of simultaneous binding to these clients (model in Figure 7), which will be a less likely scenario for our peptides due to their much shorter length. In keeping with this possibility, a recent study with cytosolic orthologues of BiP and Grp170 found that Hsp110 (Apg2) promoted a coordinated dissociation of Hsp70 and a DnaJ protein from α-synuclein amyloid fibrils in vitro (Gao et al, 2015). Further studies are needed to resolve this point.…”

The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

“…There remains debate as to whether these proteins are sequestered as a consequence of aggregation, or if there is a physiological role for their presence. The recently-described ability of the Hsp70 chaperone complex to bind and facilitate disassembly of α-syn fibrils (35), provides support for an active role of these chaperones within aggregates. Previous studies have reported that αB-c and Hsp27 (as well as other sHsps) are present in Lewy bodies (36)(37)(38)(39)(40).…”

Prions and Protein Assemblies that Convey Biological Information in Health and Disease

“…Pioneering work suggested that a mixture of Hsp70, Hsp40, and Hsp110 may disassemble amorphous aggregates but not amyloids (Nillegoda et al, 2015; Rampelt et al, 2012; Shorter, 2011). A provocative recent paper has further observed that a similar three chaperone system (Hsc70, DNAJC1, and Hsp110) cooperates to rapidly disaggregate α-synuclein fibrils into smaller seeds and monomer when present at the right stoichiometry (Gao et al, 2015). Moreover, another study has demonstrated that the serine protease HTRA1 solubilizes tau amyloids in an ATP-independent manner in vitro (Poepsel et al, 2015).…”