Molecular Mechanism for the Suppression of Alpha Synuclein Membrane Toxicity by an Unconventional Extracellular Chaperone

Alpha synuclein (alpha S) oligomers are a key component of Lewy bodies implicated in Parkinsons disease (PD). Although primarily intracellular, extracellular alpha S exocytosed from neurons also contributes to PD pathogenesis through a prion-like transmission mechanism. Here, we show at progressive degrees of resolution that the most abundantly expressed extracellular protein, human serum albumin (HSA), inhibits alpha S oligomer (alpha S-n) toxicity through a three-pronged mechanism. First, endogenous HSA targets alpha S-n with sub-mu M affinity via solvent-exposed hydrophobic sites, breaking the catalytic cycle that promotes alpha S self-association. Second, HSA remodels alpha S oligomers and high-MW fibrils into chimeric intermediates with reduced toxicity. Third, HSA unexpectedly suppresses membrane interactions with the N-terminal and central alpha S regions. Overall, our findings suggest that the extracellular proteostasis network may regulate alpha S cell-to-cell transmission not only by reducing the populations of membrane-binding competent alpha S oligomers but possibly also by shielding the membrane interface from residual toxic species.