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.
Highlights
Neurodegenerative diseases (NDDs) are a major cause of global morbidity and mortality in the elderly, and, with an ever-rising prevalence, represent one of the greatest health challenges of the 21st century
From the 7th to 17th September 2019, a systematic electronic database search was conducted on MEDLINE (OvidSP), EMBASE (OvidSP), Web of Science Core Collection, and PubMed to retrieve all experimental studies investigating the effect of Post-translational modifications (PTMs) on protein aggregation in the pre-specified
A total of 1196 articles were identified from the database search and an additional 26 potentially relevant fromwere hand-searching keythe papers
Summary
Neurodegenerative diseases (NDDs) are a major cause of global morbidity and mortality in the elderly, and, with an ever-rising prevalence, represent one of the greatest health challenges of the 21st century. NDDs encompass heterogeneous cerebral proteinopathies, characterised by a progressive loss of vulnerable neurons such that patients present with broad clinical sequelae that includes motor, behavioural, and cognitive deficits [1,2,3]. NDDs can be characterised histopathologically via hallmark intra- or extracellular accumulations of degradation-resistant protein aggregates concentrated to certain brain regions (Table 1). These protein aggregates interfere with neuronal function, and presumably induce toxicity that drives cell death [2]. Brain Sci. 2020, 10, 232; doi:10.3390/brainsci10040232 www.mdpi.com/journal/brainsci. Brain Sci. 2020, 10, 232 NDD Commonly Mutated Proteins Primary Region of Damage AD APP, presenilins
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