Extracellular α-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 α-synuclein as a biomarker has been found to be inconsistent and generally ineffective, largely due to the contribution of peripherally derived α-synuclein. In this study, we discovered, via an intracerebroventricular injection of radiolabeled α-synuclein into mouse brain, that CSF α-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 α-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 α-synuclein concentrations, which are consistently reported to be lower in PD patients compared to controls, the levels of plasma exosomal α-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 α-synuclein, a significant correlation between plasma exosomal α-synuclein and disease severity (r = 0.176, p = 0.004) was observed, and the diagnostic sensitivity and specificity achieved by plasma exosomal α-synuclein were comparable to those determined by CSF α-synuclein. Further studies are clearly needed to elucidate the mechanism involved in the transport of CNS α-synuclein to the periphery, which may lead to a more convenient and robust assessment of PD clinically.
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Acknowledgments We thank Drs. Honglian Li and Sangwoo Jung for their kind help on EM method development, and Dr. Ane Korff for her assistance in Western blot confirmation. We also deeply appreciate the patients and participants for their generous participation and donation of samples. This study was supported by generous grants from the National Institutes of Health (NIH) (U01 NS082137, P42 ES004696-5897, P30 ES007033-6364, R01 AG033398, R01 ES016873, R01 ES019277, R01 NS057567, and P50 NS062684-6221 to JZ, R01 NS065070 to CPZ, and P50 AG005131 to DRG), and partially by a pilot study award from the NIH-sponsored ADRC at the UW (P50 AG003156-30) and a National Institute of Neurological Disorders and Stroke/NIH award R21 NS085425 to MS. It was also supported in part by the University of Washington’s Proteomics Resource (UWPR95794). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
- Parkinson’s disease