Version 2 2020-05-12, 20:05Version 2 2020-05-12, 20:05
Version 1 2020-05-08, 15:34Version 1 2020-05-08, 15:34
journal contribution
posted on 2020-05-12, 20:05authored byRashik 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
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.