Hsp90 inhibits α-synuclein aggregation by interacting with soluble oligomers.
Aggregated α-synuclein is one of the main components of the pathological Lewy bodies associated with Parkinson's disease (PD). Many other proteins, including chaperones such as Hsp90 and Hsp70, have been found co-localized with Lewy bodies and the expression levels of Hsp90 have been found to be increased in brains of PD patients. Although the role of Hsp70 in the aggregation of α-synuclein has been extensively studied, relatively little is known about the effect of Hsp90 on this process. Here, we have investigated if Hsp90 can prevent the aggregation of the A53T pathological mutant of α-synuclein in vitro. A detailed study using many biophysical methods has revealed that Hsp90 prevents α-synuclein from aggregating in an ATP-independent manner and that it forms a strong complex with the transiently populated toxic oligomeric α-synuclein species formed along the aggregation pathway. We have also shown that, upon forming a complex with Hsp90, the oligomers are rendered harmless and nontoxic to cells. Thus, we have clear evidence that Hsp90 is likely to play an important role on these processes in vivo.
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
Soumya
S
Daturpalli
Christopher A
CA
Waudby
Sarah
S
Meehan
Sophie E
SE
Jackson
D000251:Adenosine Triphosphatases / Q000378:metabolism; D002460:Cell Line; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D055550:Protein Stability; D012995:Solubility; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity
D018841:HSP90 Heat-Shock Proteins; D046912:Multiprotein Complexes; D051844:alpha-Synuclein; D000251:Adenosine Triphosphatases
AFM; BFP; HSQC; ITC; PD; Parkinson's disease; QCM; TEM; ThT; aggregation; amyloid; atomic force microscopy; blue fluorescent protein; cytoprotective; heteronuclear single quantum coherence; isothermal titration calorimetry; quartz crystal microscopy; thioflavin T; thioflavin T assay; transmission electron microscopy