PMID- 32641150 OWN - NLM STAT- MEDLINE DCOM- 20210531 LR - 20240427 IS - 2051-5960 (Electronic) IS - 2051-5960 (Linking) VI - 8 IP - 1 DP - 2020 Jul 8 TI - Erythrocytic alpha-synuclein contained in microvesicles regulates astrocytic glutamate homeostasis: a new perspective on Parkinson's disease pathogenesis. PG - 102 LID - 10.1186/s40478-020-00983-w [doi] LID - 102 AB - Parkinson's disease is a neurodegenerative disorder characterized by the transmission and accumulation of toxic species of alpha-synuclein (alpha-syn). Extracellular vesicles (EVs) are believed to play a vital role in the spread of toxic alpha-syn species. Recently, peripheral alpha-syn pathology has been investigated, but little attention has been devoted to erythrocytes, which contain abundant alpha-syn. In this study, we first demonstrated that erythrocyte-derived EVs isolated from Parkinson's disease patients carried elevated levels of oligomeric alpha-syn, compared to those from healthy controls. Moreover, human erythrocyte-derived EVs, when injected into peripheral blood in a mouse model of Parkinson's disease, were found to readily cross the blood-brain barrier (BBB). These EVs accumulated in astrocyte endfeet, a component of the BBB, where they impaired glutamate uptake, likely via interaction between excitatory amino acid transporter 2 (EAAT2) and oligomeric alpha-syn. These data suggest that erythrocyte-derived EVs and the oligomeric alpha-syn carried in them may play critical roles in the progression or even initiation of Parkinson's disease. Additionally, the mechanisms involved are attributable at least in part to dysfunction of astrocytes induced by these EVs. These observations provide new insight into the understanding of the mechanisms involved in Parkinson's disease. FAU - Sheng, Lifu AU - Sheng L AUID- ORCID: 0000-0002-1800-3627 AD - Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. FAU - Stewart, Tessandra AU - Stewart T AD - Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. FAU - Yang, Dishun AU - Yang D AD - Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. AD - Department of Pathology, Peking University Health Science Centre and Third Hospital, Beijing, China. FAU - Thorland, Eric AU - Thorland E AD - Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. FAU - Soltys, David AU - Soltys D AD - Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. FAU - Aro, Patrick AU - Aro P AD - Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. FAU - Khrisat, Tarek AU - Khrisat T AD - Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. FAU - Xie, Zhiying AU - Xie Z AD - Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. FAU - Li, Na AU - Li N AD - Department of Pathology, Peking University Health Science Centre and Third Hospital, Beijing, China. FAU - Liu, Zongran AU - Liu Z AD - Department of Pathology, Peking University Health Science Centre and Third Hospital, Beijing, China. FAU - Tian, Chen AU - Tian C AD - Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. FAU - Bercow, Matthew AU - Bercow M AD - Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. FAU - Matsumoto, Junichi AU - Matsumoto J AD - Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. FAU - Zabetian, Cyrus P AU - Zabetian CP AD - Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. AD - Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. FAU - Peskind, Elaine AU - Peskind E AD - Mental Illness Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA. AD - Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA. FAU - Quinn, Joseph F AU - Quinn JF AD - Department of Neurology, Oregon Health and Science University, Portland, OR, USA. FAU - Shi, Min AU - Shi M AD - Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. mshi70@uw.edu. FAU - Zhang, Jing AU - Zhang J AD - Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. zhangj@uw.edu. AD - Department of Pathology, the First Affiliated Hospital and School of Medicine, Zhejiang University, Hangzhou, 310003, China. zhangj@uw.edu. LA - eng GR - NS104511/NH/NIH HHS/United States GR - U01 NS091272/NS/NINDS NIH HHS/United States GR - P50 AG005136/AG/NIA NIH HHS/United States GR - R21 AG060142/AG/NIA NIH HHS/United States GR - R01 AG056711/AG/NIA NIH HHS/United States GR - MH118160/NH/NIH HHS/United States GR - P50NS062684/NH/NIH HHS/United States GR - NS091272/NH/NIH HHS/United States GR - P50 NS062684/NS/NINDS NIH HHS/United States GR - P30 AG066509/AG/NIA NIH HHS/United States GR - U01 AG006781/AG/NIA NIH HHS/United States GR - R21 NS104511/NS/NINDS NIH HHS/United States GR - R01 AG061383/AG/NIA NIH HHS/United States GR - R21 MH118160/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200708 PL - England TA - Acta Neuropathol Commun JT - Acta neuropathologica communications JID - 101610673 RN - 0 (alpha-Synuclein) RN - 3KX376GY7L (Glutamic Acid) SB - IM MH - Animals MH - Astrocytes/*metabolism MH - Cell-Derived Microparticles/metabolism MH - Disease Progression MH - Erythrocytes/*metabolism MH - Glutamic Acid/*metabolism MH - Homeostasis/physiology MH - Humans MH - Mice MH - Parkinson Disease/*metabolism MH - alpha-Synuclein/*metabolism PMC - PMC7346449 OTO - NOTNLM OT - Alpha-synuclein OT - Astrocytes OT - Blood-brain barrier OT - Extracellular vesicles OT - Glutamate OT - Parkinson's disease COIS- The authors have declared that no conflict of interest exists. EDAT- 2020/07/10 06:00 MHDA- 2021/06/01 06:00 PMCR- 2020/07/08 CRDT- 2020/07/10 06:00 PHST- 2020/05/04 00:00 [received] PHST- 2020/06/29 00:00 [accepted] PHST- 2020/07/10 06:00 [entrez] PHST- 2020/07/10 06:00 [pubmed] PHST- 2021/06/01 06:00 [medline] PHST- 2020/07/08 00:00 [pmc-release] AID - 10.1186/s40478-020-00983-w [pii] AID - 983 [pii] AID - 10.1186/s40478-020-00983-w [doi] PST - epublish SO - Acta Neuropathol Commun. 2020 Jul 8;8(1):102. doi: 10.1186/s40478-020-00983-w.