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

详细信息    查看全文

• 作者：Min Shi (1)
  Changqin Liu (2)
  Travis J. Cook (3)
  Kristin M. Bullock (4) (5)
  Yanchun Zhao (1)
  Carmen Ginghina (1)
  Yanfei Li (3)
  Patrick Aro (1)
  Romel Dator (1)
  Chunmei He (6)
  Michael J. Hipp (1)
  Cyrus P. Zabetian (4) (7) (8)
  Elaine R. Peskind (10) (9)
  Shu-Ching Hu (4) (7) (8)
  Joseph F. Quinn (11)
  Douglas R. Galasko (12)
  William A. Banks (4) (5)
  Jing Zhang (1)
  
• 关键词：Parkinson’s disease ; Exosome ; α ; synuclein ; Biomarker ; Plasma
• 刊名：Acta Neuropathologica
• 出版年：2014
• 出版时间：November 2014
• 年：2014
• 卷：128
• 期：5
• 页码：639-650
• 全文大小：1,005 KB
• 参考文献：1. Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero C, Ferrer I, Obeso JA, Schapira AH (2010) Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol 67(12):1464-472 CrossRef
  2. Alvarez-Erviti L, Seow Y, Schapira AH, Gardiner C, Sargent IL, Wood MJ, Cooper JM (2011) Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis 42(3):360-67 CrossRef
  3. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29(4):341-45 CrossRef
  4. Arai Y, Yamazaki M, Mori O, Muramatsu H, Asano G, Katayama Y (2001) Alpha-synuclein-positive structures in cases with sporadic Alzheimer’s disease: morphology and its relationship to tau aggregation. Brain Res 888(2):287-96 CrossRef
  5. Banks WA, Broadwell RD (1994) Blood to brain and brain to blood passage of native horseradish peroxidase, wheat germ agglutinin, and albumin: pharmacokinetic and morphological assessments. J Neurochem 62(6):2404-419 CrossRef
  6. Banks WA, Kumar VB, Farr SA, Nakaoke R, Robinson SM, Morley JE (2011) Impairments in brain-to-blood transport of amyloid-beta and reabsorption of cerebrospinal fluid in an animal model of Alzheimer’s disease are reversed by antisense directed against amyloid-beta protein precursor. J Alzheimers Dis 23(4):599-05
  7. Barbour R, Kling K, Anderson JP, Banducci K, Cole T, Diep L, Fox M, Goldstein JM, Soriano F, Seubert P, Chilcote TJ (2008) Red blood cells are the major source of alpha-synuclein in blood. Neurodegener Dis 5(2):55-9 CrossRef
  8. Bartels AL (2011) Blood-brain barrier P-glycoprotein function in neurodegenerative disease. Curr Pharm Des 17(26):2771-777 CrossRef
  9. Chivet M, Hemming F, Pernet-Gallay K, Fraboulet S, Sadoul R (2012) Emerging role of neuronal exosomes in the central nervous system. Front Physiol 3:145 CrossRef
  10. Cholerton BA, Zabetian CP, Quinn JF, Chung KA, Peterson A, Espay AJ, Revilla FJ, Devoto J, Watson GS, Hu SC, Edwards KL, Montine TJ, Leverenz JB (2013) Pacific Northwest Udall Center of excellence clinical consortium: study design and baseline cohort characteristics. J Parkinsons Dis 3(2):205-14
  11. Chu Y, Dodiya H, Aebischer P, Olanow CW, Kordower JH (2009) Alterations in lysosomal and proteasomal markers in Parkinson’s disease: relationship to alpha-synuclein inclusions. Neurobiol Dis 35(3):385-98 CrossRef
  12. Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, Zhu L, Vanderburg CR, McLean PJ (2012) Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 7:42 CrossRef
  13. Derkinderen P, Rouaud T, Lebouvier T, Bruley des Varannes S, Neunlist M, De Giorgio R (2011) Parkinson disease: the enteric nervous system spills its guts. Neurology 77(19):1761-767 CrossRef
  14. Desai BS, Monahan AJ, Carvey PM, Hendey B (2007) Blood-brain barrier pathology in Alzheimer’s and Parkinson’s disease: implications for drug therapy. Cell Transplant 16(3):285-99 CrossRef
  15. Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA 106(31):13010-3015 CrossRef
  16. Devic I, Hwang H, Edgar JS, Izutsu K, Presl
• 作者单位：Min Shi (1)
  Changqin Liu (2)
  Travis J. Cook (3)
  Kristin M. Bullock (4) (5)
  Yanchun Zhao (1)
  Carmen Ginghina (1)
  Yanfei Li (3)
  Patrick Aro (1)
  Romel Dator (1)
  Chunmei He (6)
  Michael J. Hipp (1)
  Cyrus P. Zabetian (4) (7) (8)
  Elaine R. Peskind (10) (9)
  Shu-Ching Hu (4) (7) (8)
  Joseph F. Quinn (11)
  Douglas R. Galasko (12)
  William A. Banks (4) (5)
  Jing Zhang (1)
  
  1. Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA, 98104, USA
  2. Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, Fujian, China
  3. Department of Environmental and Occupational Health Sciences, University of Washington School of Public Health, Seattle, WA, 98195, USA
  4. Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
  5. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, 98195, USA
  6. Department of Endocrinology and Diabetes, Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, Fujian, China
  7. Parkinson’s Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
  8. Department of Neurology, University of Washington School of Medicine, Seattle, WA, 98195, USA
  10. Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
  9. Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA
  11. Department of Neurology, Oregon Health and Science University, Portland, OR, 97239, USA
  12. Department of Neurosciences, University of California at San Diego, La Jolla, CA, 92093, USA
  
• ISSN：1432-0533

文摘

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.