Arresting amyloid with coulomb's law: acetylation of ALS-linked SOD1 by aspirin impedes aggregation

Biophysical Journal
Alireza AbdolvahabiBryan F Shaw

Abstract

Although the magnitude of a protein's net charge (Z) can control its rate of self-assembly into amyloid, and its interactions with cellular membranes, the net charge of a protein is not viewed as a druggable parameter. This article demonstrates that aspirin (the quintessential acylating pharmacon) can inhibit the amyloidogenesis of superoxide dismutase (SOD1) by increasing the intrinsic net negative charge of the polypeptide, i.e., by acetylation (neutralization) of multiple lysines. The protective effects of acetylation were diminished (but not abolished) in 100 mM NaCl and were statistically significant: a total of 432 thioflavin-T amyloid assays were performed for all studied proteins. The acetylation of as few as three lysines by aspirin in A4V apo-SOD1-a variant that causes familial amyotrophic lateral sclerosis (ALS)-delayed amyloid nucleation by 38% and slowed amyloid propagation by twofold. Lysines in wild-type- and ALS-variant apo-SOD1 could also be peracetylated with aspirin after fibrillization, resulting in supercharged fibrils, with increases in formal net charge of ∼2 million units. Peracetylated SOD1 amyloid defibrillized at temperatures below unacetylated fibrils, and below the melting temperature of native Cu2,...Continue Reading

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Citations

Jul 25, 2015·ACS Chemical Neuroscience·Yunhua ShiBryan F Shaw
Apr 21, 2016·PLoS Biology·Miguel MompeánDouglas V Laurents
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Jan 11, 2020·Frontiers in Molecular Neuroscience·Liberty François-MoutalMay Khanna
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Jan 3, 2020·ACS Chemical Neuroscience·Katelyn M BaumerBryan F Shaw
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