Stable alpha-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones.
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.
Hinault
Marie-Pierre
MP
Plant Molecular Biology Department, University of Lausanne, Biophore, 1015 Lausanne, Switzerland.
Cuendet
America Farina Henriquez
AF
Mattoo
Rayees U H
RU
Mensi
Mounir
M
Dietler
Giovanni
G
Lashuel
Hilal A
HA
Goloubinoff
Pierre
P
D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D002417:Cattle; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007934:Leuconostoc / Q000737:chemistry / Q000378:metabolism; D016631:Lewy Bodies / Q000737:chemistry / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D017510:Protein Folding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D001426:Bacterial Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D051844:alpha-Synuclein