Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson's disease

Extracellular alpha-synuclein is important in the pathogenesis of Parkinson's disease (PD) and also as a potential biomarker when tested in the cerebrospinal fluid (CSF). The performance of blood plasma or serum alpha-synuclein as a biomarker has been found to be inconsistent and generally ineffective, largely due to the contribution of peripherally derived alpha-synuclein. In this study, we discovered, via an intracerebroventricular injection of radiolabeled alpha-synuclein into mouse brain, that CSF alpha-synuclein was readily transported to blood, with a small portion being contained in exosomes that are relatively specific to the central nervous system (CNS). Consequently, we developed a technique to evaluate the levels of alpha-synuclein in these exosomes in individual plasma samples. When applied to a large cohort of clinical samples (267 PD, 215 controls), we found that in contrast to CSF alpha-synuclein concentrations, which are consistently reported to be lower in PD patients compared to controls, the levels of plasma exosomal alpha-synuclein were substantially higher in PD patients, suggesting an increased efflux of the protein to the peripheral blood of these patients. Furthermore, although no association was observed between plasma exosomal and CSF alpha-synuclein, a significant correlation between plasma exosomal alpha-synuclein and disease severity (r = 0.176, p = 0.004) was observed, and the diagnostic sensitivity and specificity achieved by plasma exosomal alpha-synuclein were comparable to those determined by CSF alpha-synuclein. Further studies are clearly needed to elucidate the mechanism involved in the transport of CNS alpha-synuclein to the periphery, which may lead to a more convenient and robust assessment of PD clinically.