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 (αSn) toxicity through a three-pronged mechanism. First, endogenous HSA targets αSn 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.
Bibliographical noteFunding Information:
This project was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC RGPIN-2019-05990; RGPIN-2018-05585; RGPIN-2016-06450; RGPIN-2014-04514), partially by the National Institutes of Health (R01 GM 64742 and HL 144130 to G.V.), Canadian Institutes of Health Research (201710GSD-402345-288638 to R.A.), and the American Heart Association (19POST34420009 to D.K.W.). We thank S. Boulton, J. A. Byun, N. Jafari, Y. Lu, and R. Truant (McMaster U.) for helpful discussions and E. K. Larsen for assistance with characterization of αS oligomer species.
© 2020 American Chemical Society.
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't