Molecular Mechanism for the Suppression of Alpha Synuclein Membrane Toxicity by an Unconventional Extracellular Chaperone
Rashik Ahmed, Jinfeng Huang, Daniel K. Weber, Tata Gopinath, Gianluigi Veglia, Madoka Akimoto, Adree Khondker, Maikel C. Rheinstädter, Vincent Huynh, Ryan G. Wylie, José Carlos Bozelli, Richard M. Epand, Giuseppe Melacini
Abstract
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.