title: Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson's disease.
abstract: 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.
authors.affiliation: Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian, China.
authors.forename: Changqin
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington School of Public Health, Seattle, WA 98195, USA.
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Cook
authors.affiliation: Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.|Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Bullock
authors.affiliation: Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ginghina
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington School of Public Health, Seattle, WA 98195, USA.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aro
authors.affiliation: Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.
authors.forename: Romel
authors.initials: R
authors.lastname: Dator
authors.affiliation: Department of Endocrinology and Diabetes and Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hipp
authors.affiliation: Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.|Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.|Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Cyrus P
authors.initials: CP
authors.lastname: Zabetian
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.|Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Peskind
authors.affiliation: Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.|Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.|Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Hu
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Quinn
authors.affiliation: Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Galasko
authors.affiliation: Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.|Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
authors.affiliation: Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D055354:Exosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008854:Microscopy, Electron; D008875:Middle Aged; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D010300:Parkinson Disease / Q000097:blood / Q000134:cerebrospinal fluid; D012372:ROC Curve; D051844:alpha-Synuclein / Q000097:blood* / Q000134:cerebrospinal fluid*
chemical_list: D039842:Neural Cell Adhesion Molecule L1; D051844:alpha-Synuclein