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

Research output: Contribution to journalArticle

48 Citations (Scopus)

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

Fingerprint

Synucleins
Dopaminergic Neurons
Oligomers
Parkinson Disease
Lewy Bodies
Poisons
Population Dynamics
Neurodegenerative Diseases
Neurons
Complement System Proteins
Homeostasis
Adenosine Triphosphate
Apoptosis
Peptides
Neurodegenerative diseases
Proteins
Agglomeration
Monomers
Tissue
Substrates

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

Stable α-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones. / Hinault, Marie Pierre; Cuendet, America Farina Henriquez; Mattoo, Rayees U H; Mensi, Mounir; Dietler, Giovanni; Lashuel, Hilal A.; Goloubinoff, Pierre.

In: Journal of Biological Chemistry, Vol. 285, No. 49, 03.12.2010, p. 38173-38182.

Research output: Contribution to journalArticle

Hinault, MP, Cuendet, AFH, Mattoo, RUH, Mensi, M, Dietler, G, Lashuel, HA & 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, vol. 285, no. 49, pp. 38173-38182. https://doi.org/10.1074/jbc.M110.127753
Hinault, Marie Pierre ; Cuendet, America Farina Henriquez ; Mattoo, Rayees U H ; Mensi, Mounir ; Dietler, Giovanni ; Lashuel, Hilal A. ; Goloubinoff, Pierre. / Stable α-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 49. pp. 38173-38182.
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