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

Détails

ID Serval
serval:BIB_AE630F744A32
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Stable alpha-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones.
Périodique
Journal of Biological Chemistry
Auteur(s)
Hinault M.P., Cuendet A.F., Mattoo R.U., Mensi M., Dietler G., Lashuel H.A., Goloubinoff P.
ISSN
1083-351X (Electronic)
ISSN-L
0021-9258
Statut éditorial
Publié
Date de publication
2010
Volume
285
Numéro
49
Pages
38173-38182
Langue
anglais
Résumé
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.
Mots-clé
Animals, Apoptosis, Bacterial Proteins/chemistry, Bacterial Proteins/metabolism, Cattle, HSP40 Heat-Shock Proteins/chemistry, HSP40 Heat-Shock Proteins/metabolism, HSP70 Heat-Shock Proteins/chemistry, HSP70 Heat-Shock Proteins/genetics, Homeostasis, Humans, Leuconostoc/chemistry, Leuconostoc/metabolism, Lewy Bodies/chemistry, Lewy Bodies/metabolism, Neurons/metabolism, Parkinson Disease/metabolism, Protein Folding, Protein Multimerization, Protein Structure, Tertiary, alpha-Synuclein/chemistry, alpha-Synuclein/genetics
Pubmed
Web of science
Open Access
Oui
Création de la notice
18/05/2011 10:29
Dernière modification de la notice
20/08/2019 16:18
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