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

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.

Keywords: neurodegenerative diseases; neurotoxicity; post-translational modifications; protein aggregates.

Figure 1

Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow chart detailing the stages of study retrieval and selection [94].

Figure 2

Schematic representation of beta-amyloid-42 peptide illustrating PTMs and respective amino acid residues.

Figure 3

Schematic representation of tau protein illustrating PTMs and respective amino acid residues.

Figure 4

Schematic representation of α-synuclein illustrating PTMs and respective amino acid residues.

Figure 5

Schematic representation of TDP-43 illustrating PTMs and respective amino acid residues.

Figure 6

Schematic representation of SOD1 illustrating PTMs and respective amino acid residues. * Due to their importance for SOD1 structural stability, metal-binding sites, and residues involved in disulphide bond formation are also marked.

Figure 7

Schematic representation of huntingtin illustrating PTMs and respective amino acid residues.

Figure 8

Schematic representation of ataxin-3 illustrating PTMs and respective amino acid residues.

Figure 9

Schematic representation of PrP^c illustrating PTMs and respective amino acid residues.