Alpha-synuclein in skin as a high-quality biomarker for Parkinson's disease

Parkinson's disease (PD), the most common neurological motor system disorder, which characterised by the irreversible loss of dopaminergic neurones in the substantia nigra pars compacta, and leads to the deficiency of dopamine in the striatum. Deposited Lewy bodies (LBs) in diseased neurones and nerve terminals are the pathological hallmark of PD, and alpha-synuclein (α-Syn) is the most prominent protein in LBs. The tight association between α-Syn and the molecular pathology of PD has generatly increaed the interest in using the α-Syn species as biomarkers to diagnose early PD. α-Syn is not confined to the central nervous system, it is also present in the peripheral tissues, such as human skin. The assessment of skin α-Syn has the potential to be a diagnostic method that not only has excellent sensitivity, specificity, and reproducibility, but also convenient and acceptable to patients. In this review, we (i) integrate the biochemical, aggregation and structural features of α-Syn; (ii) map the distribution of the α-Syn species present in the brain, biological fluids, and peripheral tissues; and (iii) present a critical and comparative analysis of previous studies that have measured α-Syn in the skin. Finally, we provide an outlook on the future of skin biopsy as a diagnostic approach for PD, and highlight its potential implications for clinical trials, clinical decision-making, treatment strategies as well as the development of new therapies.