Alpha-synuclein pathobiology and therapeutic targeting in Parkinson’s disease

Background and purpose: Alpha-synuclein (α-Syn) is a presynaptic protein involved in synaptic vesicle trafficking, neurotransmitter release, and membrane remodelling. Its misfolding and pathological aggregation are central to Parkinson’s disease (PD) and related synucleinopathies. This review examines how structural changes, post-translational modifications (PTMs), and interactions with proteins, lipids, metal ions, and cellular organelles regulate α-Syn function and contribute to neurodegeneration and evaluates the implications of these mechanisms for biomarker development and therapeutic targeting. Experimental approach: This review synthesizes and critically discusses existing literature on α-Syn structure and physiological functions, molecular interactions, aggregation pathways, cellular toxicity, and the roles of PTMs in protein homeostasis and disease progression. It also evaluates emerging diagnostic approaches, including seed amplification assays and analyses of cerebrospinal fluid, blood, and extracellular vesicles, alongside therapeutic strategies targeting α-Syn aggregation, clearance, and expression. Key results: The reviewed evidence indicates that α-Syn pathobiology arises from the interplay of conformational plasticity, molecular interactions, PTMs, and impaired cellular proteostasis. These processes contribute to mitochondrial dysfunction, lysosomal impairment, neuroinflammation, and the propagation of pathological α-Syn assemblies. Seed amplification assays and other molecular biomarker approaches show promise for improving detection and characterization of synucleino­pathies, while immunotherapies, aggregation inhibitors, gene-based interventions, and strategies that enhance protein clearance represent potential disease-modifying approaches. However, diagnostic standardization and the demonstration of unequivocal clinical efficacy remain important challenges. Conclusion: Integrating α-Syn molecular biology with advances in biomarker development and therapeutic research provides a framework for understanding disease heterogeneity and identifying mechanism-based interventions. This review highlights the need to move beyond reducing α-Syn burden toward selectively preventing pathogenic conformations while preserving its physiological functions. Further validation in clinical studies is essential to establish the diagnostic utility and therapeutic effectiveness of these approaches.