Synuclein Proteoforms: Role in Health and Disease

Synucleins α, β, and γ are inherently disordered proteins that play essential roles in neuronal physiology and are increasingly recognized as key players in neurodegenerative disease mechanisms. The molecular basis of synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, is the pathological aggregation and misfolding of synucleins. However, the biological significance of the diverse synuclein proteoforms that result from alternative splicing, extensive post-translational modifications, and conformational heterogeneity is still not fully understood. This review systematically incorporates current knowledge of the structural and functional diversity of synuclein proteoforms, highlighting their molecular interactions and aggregation pathways. We investigate the regulatory effects of β and γ-synucleins (β-syn and γ-syn), which have different physiological functions and clinical applications in addition to influencing α-synuclein (α-syn) aggregation. In addition to synucleins' involvement in the central nervous system, recent findings show their role in immune regulation and functions in peripheral tissues, highlighting their systemic relevance. Controversial aspects, such as the mechanisms of prion-like propagation, proteoform-specific toxicity, and differential cellular vulnerability, are thoroughly analyzed. Synuclein proteoforms have been thoroughly characterized due to developments in molecular imaging and proteomic techniques, opening the door for targeted treatment approaches. Developing novel treatments for mitigating the progression of synucleinopathies and enhancing patient outcomes requires an understanding of the complex biology of synuclein proteoforms. The goal of this study is to present a thorough framework that connects translational research and molecular neurobiology in disorders related to synuclein.