Stable α-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones

Marie Pierre Hinault, America Farina Henriquez Cuendet, Rayees U H Mattoo, Mounir Mensi, Giovanni Dietler, Hilal A. Lashuel, Pierre Goloubinoff

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Abstract

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.

Original languageEnglish
Pages (from-to)38173-38182
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number49
DOIs
Publication statusPublished - 3 Dec 2010
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Hinault, M. P., Cuendet, A. F. H., Mattoo, R. U. H., Mensi, M., Dietler, G., Lashuel, H. A., & Goloubinoff, P. (2010). Stable α-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones. Journal of Biological Chemistry, 285(49), 38173-38182. https://doi.org/10.1074/jbc.M110.127753