Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and nonmotor manifestations that reflect widespread neuronal dysfunction. A central pathological feature of PD is the misfolding, aggregation, and propagation of alpha-synuclein (α-syn), a presynaptic neuronal protein that constitutes the major component of Lewy bodies and Lewy neurites. Growing molecular, genetic, and neuropathological evidence has positioned α-syn not only as a key driver of disease pathogenesis but also as a promising biomarker for PD diagnosis, staging, and progression monitoring. This article reviews the biological rationale for targeting α-syn as a biomarker and summarizes current diagnostic approaches for its detection across different biospecimens. Advances in ultrasensitive seed amplification assays, including real-time quaking-induced conversion and protein misfolding cyclic amplification, have enabled reliable detection of pathogenic α-syn aggregates in cerebrospinal fluid, skin biopsies, blood-derived components, and peripheral biofluids such as saliva. These techniques demonstrate high sensitivity and specificity and show strong concordance with clinical phenotypes and disease severity. Integration of α-syn-based biomarkers with established clinical diagnostic criteria and emerging biological staging systems has the potential to redefine PD as a biologically defined disorder rather than a purely clinical syndrome. Nevertheless, challenges remain, including assay standardization, inter-laboratory reproducibility, accessibility in routine clinical practice, and interpretation across different synucleinopathies. Overall, α-syn-based biomarkers represent a transformative step toward earlier diagnosis, improved patient stratification, and precision medicine approaches in PD. Continued validation in large, longitudinal cohorts will be essential for their widespread clinical implementation.