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Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson's disease.
Acta Neuropathol. 2014 Nov; 128(5):639-650.AN

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+Show Affiliations

Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian, China.Department of Environmental and Occupational Health Sciences, University of Washington School of Public Health, Seattle, WA 98195, USA.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.Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.Department of Environmental and Occupational Health Sciences, University of Washington School of Public Health, Seattle, WA 98195, USA.Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.Department of Endocrinology and Diabetes and Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian, China.Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.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.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.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.Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093, USA.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.Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24997849

Citation

Shi, Min, et al. "Plasma Exosomal Α-synuclein Is Likely CNS-derived and Increased in Parkinson's Disease." Acta Neuropathologica, vol. 128, no. 5, 2014, pp. 639-650.
Shi M, Liu C, Cook TJ, et al. Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson's disease. Acta Neuropathol. 2014;128(5):639-650.
Shi, M., Liu, C., Cook, T. J., Bullock, K. M., Zhao, Y., Ginghina, C., Li, Y., Aro, P., Dator, R., He, C., Hipp, M. J., Zabetian, C. P., Peskind, E. R., Hu, S. C., Quinn, J. F., Galasko, D. R., Banks, W. A., & Zhang, J. (2014). Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson's disease. Acta Neuropathologica, 128(5), 639-650. https://doi.org/10.1007/s00401-014-1314-y
Shi M, et al. Plasma Exosomal Α-synuclein Is Likely CNS-derived and Increased in Parkinson's Disease. Acta Neuropathol. 2014;128(5):639-650. PubMed PMID: 24997849.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson's disease. AU - Shi,Min, AU - Liu,Changqin, AU - Cook,Travis J, AU - Bullock,Kristin M, AU - Zhao,Yanchun, AU - Ginghina,Carmen, AU - Li,Yanfei, AU - Aro,Patrick, AU - Dator,Romel, AU - He,Chunmei, AU - Hipp,Michael J, AU - Zabetian,Cyrus P, AU - Peskind,Elaine R, AU - Hu,Shu-Ching, AU - Quinn,Joseph F, AU - Galasko,Douglas R, AU - Banks,William A, AU - Zhang,Jing, Y1 - 2014/07/06/ PY - 2014/05/13/received PY - 2014/06/19/accepted PY - 2014/06/18/revised PY - 2014/7/7/entrez PY - 2014/7/7/pubmed PY - 2015/6/16/medline SP - 639 EP - 650 JF - Acta neuropathologica JO - Acta Neuropathol VL - 128 IS - 5 N2 - 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. SN - 1432-0533 UR - https://www.unboundmedicine.com/medline/citation/24997849/Plasma_exosomal_α_synuclein_is_likely_CNS_derived_and_increased_in_Parkinson's_disease_ L2 - https://dx.doi.org/10.1007/s00401-014-1314-y DB - PRIME DP - Unbound Medicine ER -