This SI focuses on the α-synucleinopathy spectrum, including Parkinson’s disease and dementia with Lewy bodies, highlighting pathological propagation, protein homeostasis/autophagy-lysosomal pathways, mitochondria–inflammation interactions, and stratified mechanisms driven by genetic subtypes such as LRRK2 and GBA. We welcome original research and reviews on mechanistic studies, fluid and imaging biomarkers, translational models, and clinical trial design, with particular interest in immunotherapies (active or passive), lysosomal/endocytic-targeted strategies, and disease-modifying interventions related to metabolic or anti-aging pathways. Contributions addressing early and prodromal stage definitions, endpoints, follow-up strategies, and shared protein clearance frameworks across diseases are encouraged.