Heat shock protein 70 inhibits alpha-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 (alphaSyn). Although the detailed mechanisms remain unclear, mounting evidence suggests that the misfolding of alphaSyn 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 alphaSyn fibril formation via preferential binding to prefibrillar species. Moreover, our studies reveal that Hsp70 alters the characteristics of toxic alphaSyn aggregates and indicate that cellular toxicity arises from the prefibrillar forms of alphaSyn. 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.
Dedmon
Matthew M
MM
Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, United Kingdom.
Christodoulou
John
J
Wilson
Mark R
MR
Dobson
Christopher M
CM
D052160:Benzothiazoles; D002850:Chromatography, Gel; D002942:Circular Dichroism; D005434:Flow Cytometry; D005822:Genetic Vectors; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000737:chemistry; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013347:Subcellular Fractions / Q000378:metabolism; D051843:Synucleins; D013844:Thiazoles / Q000737:chemistry; D013997:Time Factors; D051844:alpha-Synuclein
D052160:Benzothiazoles; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T