Heat shock protein 70 inhibits α-synuclein fibril formation via preferential binding to prefibrillar species

Parkinson's disease (PD) is a neurodegenerative disorder affecting an estimated 4 million people worldwide. Intracellular proteinaceous inclusions called Lewy bodies are the histological hallmarks of PD and are primarily composed of aggregated alpha-synuclein (alpha Syn). Although the detailed mechanisms remain unclear, mounting evidence suggests that the misfolding of alpha Syn into prefibrillar and fibrillar species is the driving force responsible for cellular toxicity. We show here that the molecular chaperone heat shock protein (Hsp) 70 strongly inhibits alpha Syn fibril formation via preferential binding to prefibrillar species. Moreover, our studies reveal that Hsp70 alters the characteristics of toxic alpha Syn aggregates and indicate that cellular toxicity arises from the prefibrillar forms of alpha Syn. This work therefore elucidates a specific role of Hsp70 in the pathogenesis of PD and supports the general concept that chaperone action is a crucial aspect in protecting against the otherwise damaging consequences of protein misfolding.