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

Details

Serval ID
serval:BIB_AE630F744A32
Type
Article: article from journal or magazin.
Collection
Publications
Title
Stable alpha-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones.
Journal
Journal of Biological Chemistry
Author(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
Publication state
Published
Issued date
2010
Volume
285
Number
49
Pages
38173-38182
Language
english
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.
Keywords
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
Yes
Create date
18/05/2011 10:29
Last modification date
20/08/2019 16:18
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