Seeing Invisible Oligomers: Rethinking α‐Synuclein Pathology Through Proximity Ligation Assay

Parkinson's disease (PD) and multiple system atrophy are defined by α‐synuclein (αSYN)‐positive inclusions – Lewy bodies (LBs) and glial cytoplasmic inclusions – yet mounting evidence indicates that these inclusions represent only a fraction of disease‐relevant pathology. αSYN exists in dynamic conformational states, and soluble oligomeric assemblies, often undetectable by conventional immunohistochemistry, are increasingly implicated as key neurotoxic species. The αSYN proximity ligation assay (αSYN‐PLA) enables in situ detection of widespread non‐inclusion oligomeric pathology across synucleinopathies. Notably, PLA studies in LRRK2 ‐associated PD demonstrate abundant oligomeric αSYN even in cases lacking LBs, challenging the centrality of inclusions in defining disease. In this Perspective, we outline the principles of αSYN‐PLA, discuss antibody strategies and structural implications of detected species, review current evidence – including LB‐negative LRRK2 ‐PD – and consider temporal dynamics and clinical applications of PLA‐positive aggregates as biomarkers and therapeutic targets.