Stable α-Synuclein Oligomers Strongly Inhibit Chaperone Activity of the Hsp70 System by Weak Interactions with J-domain Co-chaperones

• Published in: The Journal of biological chemistry 2010-12, Vol.285 (49), p.38173-38182
• Main Authors: Hinault, Marie-Pierre, Cuendet, America Farina Henriquez, Mattoo, Rayees U.H., Mensi, Mounir, Dietler, Giovanni, Lashuel, Hilal A., Goloubinoff, Pierre
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - chemistry; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Amyloid; Animals; Apoptosis; Atomic Force Microscopy; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Cattle; Chaperone Chaperonin; Homeostasis; HSP40 Heat-Shock Proteins - chemistry; HSP40 Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - chemistry; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Humans; Leuconostoc - chemistry; Leuconostoc - metabolism; Lewy Bodies - chemistry; Lewy Bodies - metabolism; Neurodegeneration; Neurons - metabolism; Parkinson Disease; Parkinson Disease - metabolism; Protein Conformation; Protein Folding; Protein Multimerization; Protein Structure and Folding; Protein Structure, Tertiary
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.127753

α-Synuclein aggregation and accumulation in Lewy bodies are implicated in progressive loss of dopaminergic neurons in Parkinson disease and related disorders. In neurons, the Hsp70s and their Hsp40-like J-domain co-chaperones are the only known components of chaperone network that can use ATP to convert cytotoxic protein aggregates into harmless natively refolded polypeptides. Here we developed a protocol for preparing a homogeneous population of highly stable β-sheet enriched toroid-shaped α-Syn oligomers with a diameter typical of toxic pore-forming oligomers. These oligomers were partially resistant to in vitro unfolding by the bacterial Hsp70 chaperone system (DnaK, DnaJ, GrpE). Moreover, both bacterial and human Hsp70/Hsp40 unfolding/refolding activities of model chaperone substrates were strongly inhibited by the oligomers but, remarkably, not by unstructured α-Syn monomers even in large excess. The oligomers acted as a specific competitive inhibitor of the J-domain co-chaperones, indicating that J-domain co-chaperones may preferably bind to exposed bulky misfolded structures in misfolded proteins and, thus, complement Hsp70s that bind to extended segments. Together, our findings suggest that inhibition of the Hsp70/Hsp40 chaperone system by α-Syn oligomers may contribute to the disruption of protein homeostasis in dopaminergic neurons, leading to apoptosis and tissue loss in Parkinson disease and related neurodegenerative diseases.