title: Hsc70 protein interaction with soluble and fibrillar alpha-synuclein.
abstract: The aggregation of α-synuclein (α-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 α-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 α-Syn aggregation has been notably investigated. The constitutively expressed chaperone Hsc70 acts as an antiaggregation barrier before cells are overwhelmed with α-Syn aggregates and Hsp70 expression induced. Here, we investigate the interaction between Hsc70 and α-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 α-Syn in an assembly incompetent complex in the absence of ATP. The affinity of Hsc70 for soluble α-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 α-Syn assembly inhibition by Hsc70. We show that Hsc70 binds α-Syn fibrils with a 5-fold tighter affinity compared with soluble α-Syn. This suggests that Hsc70 preferentially interacts with high molecular weight α-Syn assemblies in vivo. Hsc70 binding certainly has an impact on the physicochemical properties of α-Syn assemblies. We show a reduced cellular toxicity of α-Syn fibrils coated with Hsc70 compared with "naked" fibrils. Hsc70 may therefore significantly affect the cellular propagation of α-Syn aggregates and their spread throughout the central nervous system in Parkinson disease.
authors.affiliation: Laboratoire d'Enzymologie et Biochimie Structurales, CNRS, 91198 Gif-sur-Yvette, France.
authors.forename: Samantha
authors.initials: S
authors.lastname: Pemberton
authors.forename: Karine
authors.initials: K
authors.lastname: Madiona
authors.forename: Laura
authors.initials: L
authors.lastname: Pieri
authors.forename: Mehdi
authors.initials: M
authors.lastname: Kabani
authors.forename: Luc
authors.initials: L
authors.lastname: Bousset
authors.forename: Ronald
authors.initials: R
authors.lastname: Melki
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D010300:Parkinson Disease / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D012995:Solubility; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D000682:Amyloid; C494639:Dnaja1 protein, mouse; C494641:Dnajb1 protein, mouse; D050883:HSC70 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D051844:alpha-Synuclein; D000255:Adenosine Triphosphate