Post-Translational Modifications of α-Synuclein: Drivers of Aggregation and Synucleinopathy Pathogenesis: A Systematic Review

Abstract

Aims: This systematic review aimed to critically evaluate the influence of post-translational modifications (PTMs) on α-synuclein structure, aggregation, and toxicity, and to clarify their relevance to the pathogenesis of Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Methodology: Relevant peer-reviewed literature from Scopus, web of science, PubMed, google scholar was systematically examined to assess the effects of major α-synuclein PTMs, including major enzymatic and oxidative PTMs, and their effects on protein folding, solubility, aggregation behaviour, neurotoxicity, and clearance mechanisms involving autophagy and the proteasome. Results: Phosphorylation at Serine 129 (Ser129) was identified as the most prevalent pathological modification, showing marked enrichment in aggregated α-synuclein within diseased brain tissue. Phosphorylation at Serine 87 (Ser87) and N-terminal acetylation were commonly associated with delayed fibril formation and reduced aggregation propensity, highlighting that certain PTMs exert stabilizing and aggregation-inhibitory effects on α-synuclein. Modifications such as C-terminal truncation and tyrosine nitration significantly enhanced fibrillization and promoted the formation of highly neurotoxic oligomeric species. Discussion: There are Multiple studies, that demonstrated PTM crosstalk, wherein combinations of modifications either exacerbated or mitigated aggregation and influenced degradation pathways. PTM-specific α-synuclein species, particularly phosphorylated and truncated forms, showed promise as biomarkers for early diagnosis, disease staging, and differentiation among synucleinopathies. Conclusion: Collectively, the findings indicate that α-synuclein aggregation and associated neurotoxicity result from a complex interplay of multiple post-translational modifications rather than a single pathogenic event. Elucidating this PTM network provides critical insights into disease mechanisms and supports the development of refined diagnostic approaches and targeted therapeutic interventions, including PTM-informed biomarker strategies and precision therapeutic design.