α-Synuclein-Targeted Immunotherapies in Parkinson's Disease: In Silico, In Vitro and Clinical Perspectives.

α-synuclein (α-syn) aggregation in dopaminergic neurons is a central event in Parkinson's disease (PD) pathogenesis. Immunotherapeutic strategies targeting α-syn, including passive and active approaches, aim to inhibit aggregation, propagation, and toxicity of pathological species while promoting their clearance via immune mechanisms. This review summarizes α-syn directed immunotherapies evaluated in in silico, in vitro, and in vivo models, as well as early phase clinical trials, focusing on how epitope selection and antibody formats influence efficacy, safety, and target engagement. Data on monoclonal antibody, peptide, and protein-based vaccines, and structure-guided immunogens were analyzed, integrating behavioral, neuropathological, proteomic, and structural outcomes alongside biomarker development for α-syn species in cerebrospinal fluid and peripheral compartments. Clinical evidence indicates that several candidates induce sustained anti-α-syn antibody responses with acceptable safety profiles and signs of pharmacodynamic engagement, including reductions in free or oligomeric α-syn. However, consistent long-term clinical benefits remain unproven, highlighting the gap between preclinical success and disease modification in humans. Advances in structural biology and proteomics support rational epitope selection and improved immunogen design, reinforcing α-syn-targeted immunotherapy as a promising yet experimental strategy for PD, and highlighting the need for mechanistically oriented, biomarker-driven clinical trials initiated in well-characterized prodromal and early-stage cohorts.