Molecular Mechanism for the Suppression of Alpha Synuclein Membrane Toxicity by an Unconventional Extracellular Chaperone. J Am Chem Soc 2020 May 27;142(21):9686-9699
Date
05/10/2020Pubmed ID
32383602DOI
10.1021/jacs.0c01894Scopus ID
2-s2.0-85085657558 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
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.
Author List
Ahmed R, Huang J, Weber DK, Gopinath T, Veglia G, Akimoto M, Khondker A, Rheinstädter MC, Huynh V, Wylie RG, Bozelli JC Jr, Epand RM, Melacini GAuthor
Gopinath Tata PhD Assistant Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cell Line, TumorCell Survival
Humans
Hydrophobic and Hydrophilic Interactions
Molecular Chaperones
Serum Albumin, Human
alpha-Synuclein
