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

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

Journal of the American Chemical Society (2020-05-10)
Rashik Ahmed, Jinfeng Huang, Daniel K Weber, Tata Gopinath, Gianluigi Veglia, Madoka Akimoto, Adree Khondker, Maikel C Rheinstädter, Vincent Huynh, Ryan G Wylie, José C Bozelli, Richard M Epand, Giuseppe Melacini
ABSTRACT

Alpha synuclein (αS) oligomers are a key component of Lewy bodies implicated in Parkinson's disease (PD). Although primarily intracellular, extracellular αS 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 αS oligomer (αS n ) toxicity through a three-pronged mechanism. First, endogenous HSA targets αS n with sub-μM affinity via solvent-exposed hydrophobic sites, breaking the catalytic cycle that promotes αS self-association. Second, HSA remodels αS oligomers and high-MW fibrils into chimeric intermediates with reduced toxicity. Third, HSA unexpectedly suppresses membrane interactions with the N-terminal and central αS regions. Overall, our findings suggest that the extracellular proteostasis network may regulate αS cell-to-cell transmission not only by reducing the populations of membrane-binding competent αS oligomers but possibly also by shielding the membrane interface from residual toxic species.

MATERIALS
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Avanti
18:1 PS (DOPS), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (sodium salt), chloroform