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Do Post-Translational Modifications Influence Protein Aggregation in Neurodegenerative Diseases: A Systematic Review

Schaffert, Larissa-Nele; Carter, Wayne G.

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Authors

Larissa-Nele Schaffert



Abstract

The accumulation of abnormal protein aggregates represents a universal hallmark of neurodegenerative diseases (NDDs). Post-translational modifications (PTMs) regulate protein structure and function. Dysregulated PTMs may influence the propensity for protein aggregation in NDD-proteinopathies. To investigate this, we systematically reviewed the literature to evaluate effects of PTMs on aggregation propensity for major proteins linked to the pathogenesis and/or progression of NDDs. A search of PubMed, MEDLINE, EMBASE, and Web of Science Core Collection was conducted to retrieve studies that investigated an association between PTMs and protein aggregation in seven NDDs: Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxias, transmissible spongiform encephalopathy, and multiple sclerosis. Together, 1222 studies were identified, of which 69 met eligibility criteria. We identified that the following PTMs, in isolation or combination, potentially act as modulators of proteinopathy in NDDs: isoaspartate formation in Aβ, phosphorylation of Aβ or tau in AD; acetylation, 4-hydroxy-2-neonal modification, O-GlcNAcylation or phosphorylation of α-synuclein in PD; acetylation or phosphorylation of TAR DNA-binding protein-43 in ALS, and SUMOylation of superoxide dismutase-1 in ALS; and phosphorylation of huntingtin in HD. The potential pharmacological manipulation of these aggregation-modulating PTMs represents an as-yet untapped source of therapy to treat NDDs.

Journal Article Type Article
Acceptance Date Apr 7, 2020
Online Publication Date Apr 11, 2020
Publication Date Apr 11, 2020
Deposit Date Apr 7, 2020
Publicly Available Date Apr 19, 2020
Journal Brain Sciences
Electronic ISSN 2076-3425
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 10
Issue 4
Article Number 232
DOI https://doi.org/10.3390/brainsci10040232
Public URL https://nottingham-repository.worktribe.com/output/4266377
Publisher URL https://www.mdpi.com/2076-3425/10/4/232