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Antioxid Redox Signal. 2017 Dec 10;27(17):1383-1396. doi: 10.1089/ars.2016.6978. Epub 2017 Jun 28.

Aspirin-Mediated Acetylation Protects Against Multiple Neurodegenerative Pathologies by Impeding Protein Aggregation.

Author information

1
1 Central Arkansas Veterans Healthcare System, Research & Development Service , Little Rock, Arkansas.
2
2 Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences , Little Rock, Arkansas.
3
3 Bioinformatics Program, University of Arkansas for Medical Sciences, and University of Arkansas at Little Rock , Little Rock, Arkansas.
4
4 Divison of Cardiology, Department of Medicine, University of Arkansas for Medical Sciences , Little Rock, Arkansas.

Abstract

AIMS:

Many progressive neurological disorders, including Alzheimer's disease (AD), Huntington's disease, and Parkinson's disease (PD), are characterized by accumulation of insoluble protein aggregates. In prospective trials, the cyclooxygenase inhibitor aspirin (acetylsalicylic acid) reduced the risk of AD and PD, as well as cardiovascular events and many late-onset cancers. Considering the role played by protein hyperphosphorylation in aggregation and neurodegenerative diseases, and aspirin's known ability to donate acetyl groups, we asked whether aspirin might reduce both phosphorylation and aggregation by acetylating protein targets.

RESULTS:

Aspirin was substantially more effective than salicylate in reducing or delaying aggregation in human neuroblastoma cells grown in vitro, and in Caenorhabditis elegans models of human neurodegenerative diseases in vivo. Aspirin acetylates many proteins, while reducing phosphorylation, suggesting that acetylation may oppose phosphorylation. Surprisingly, acetylated proteins were largely excluded from compact aggregates. Molecular-dynamic simulations indicate that acetylation of amyloid peptide energetically disfavors its association into dimers and octamers, and oligomers that do form are less compact and stable than those comprising unacetylated peptides.

INNOVATION:

Hyperphosphorylation predisposes certain proteins to aggregate (e.g., tau, α-synuclein, and transactive response DNA-binding protein 43 [TDP-43]), and it is a critical pathogenic marker in both cardiovascular and neurodegenerative diseases. We present novel evidence that acetylated proteins are underrepresented in protein aggregates, and that aggregation varies inversely with acetylation propensity after diverse genetic and pharmacologic interventions.

CONCLUSIONS:

These results are consistent with the hypothesis that aspirin inhibits protein aggregation and the ensuing toxicity of aggregates through its acetyl-donating activity. This mechanism may contribute to the neuro-protective, cardio-protective, and life-prolonging effects of aspirin. Antioxid. Redox Signal. 27, 1383-1396.

KEYWORDS:

(protein) acetylation; (protein) aggregation; (protein) phosphorylation; aspirin (acetylsalicylic acid); inflammation; neurodegeneration

PMID:
28537433
PMCID:
PMC5661865
DOI:
10.1089/ars.2016.6978
[Indexed for MEDLINE]
Free PMC Article

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