Hsc70 protein interaction with soluble and fibrillar alpha-synuclein.

ABSTRACT: The aggregation of ?-synuclein (?-Syn), the primary component of Lewy bodies, into high molecular weight assemblies is strongly associated with Parkinson disease. This event is believed to result from a conformational change within native ?-Syn. Molecular chaperones exert critical housekeeping functions in vivo including refolding, maintaining in a soluble state, and/or pacifying protein aggregates. The influence of the stress-induced heat shock protein 70 (Hsp70) on ?-Syn aggregation has been notably investigated. The constitutively expressed chaperone Hsc70 acts as an antiaggregation barrier before cells are overwhelmed with ?-Syn aggregates and Hsp70 expression induced. Here, we investigate the interaction between Hsc70 and ?-Syn, the consequences of this interaction, and the role of nucleotides and co-chaperones Hdj1 and Hdj2 as modulators. We show that Hsc70 sequesters soluble ?-Syn in an assembly incompetent complex in the absence of ATP. The affinity of Hsc70 for soluble ?-Syn diminishes upon addition of ATP alone or together with its co-chaperones Hdj1 or Hdj2 allowing faster binding and release of client proteins thus abolishing ?-Syn assembly inhibition by Hsc70. We show that Hsc70 binds ?-Syn fibrils with a 5-fold tighter affinity compared with soluble ?-Syn. This suggests that Hsc70 preferentially interacts with high molecular weight ?-Syn assemblies in vivo. Hsc70 binding certainly has an impact on the physicochemical properties of ?-Syn assemblies. We show a reduced cellular toxicity of ?-Syn fibrils coated with Hsc70 compared with "naked" fibrils. Hsc70 may therefore significantly affect the cellular propagation of ?-Syn aggregates and their spread throughout the central nervous system in Parkinson disease.

SUBMITTER: Pemberton S 

PROVIDER: S-EPMC3186418 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature