@article{6af37a9effc44544a723b08bb3483a6f,
title = "Erythrocytic α-synuclein contained in microvesicles regulates astrocytic glutamate homeostasis: A new perspective on Parkinson's disease pathogenesis",
abstract = "Parkinson's disease is a neurodegenerative disorder characterized by the transmission and accumulation of toxic species of α-synuclein (α-syn). Extracellular vesicles (EVs) are believed to play a vital role in the spread of toxic α-syn species. Recently, peripheral α-syn pathology has been investigated, but little attention has been devoted to erythrocytes, which contain abundant α-syn. In this study, we first demonstrated that erythrocyte-derived EVs isolated from Parkinson's disease patients carried elevated levels of oligomeric α-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 α-syn. These data suggest that erythrocyte-derived EVs and the oligomeric α-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.",
keywords = "Alpha-synuclein, Astrocytes, Blood-brain barrier, Extracellular vesicles, Glutamate, Parkinson's disease",
author = "Lifu Sheng and Tessandra Stewart and Dishun Yang and Eric Thorland and David Soltys and Patrick Aro and Tarek Khrisat and Zhiying Xie and Na Li and Zongran Liu and Chen Tian and Matthew Bercow and Junichi Matsumoto and Zabetian, {Cyrus P.} and Elaine Peskind and Quinn, {Joseph F.} and Min Shi and Jing Zhang",
note = "Funding Information: This work was funded by grants from the National Institutes of Health (NIH) (R21 NS104511, R01 AG056711, and U01 NS091272 to J.Z. and M.S., and R21 MH118160 to J.Z. and T.S.) and grants from China (NSFC81671187 and 2016YFC1306502 to J.Z., for some of the validation studies). Autopsy materials used in this study were obtained from the University of Washington Neuropathology Core, which is supported by the Alzheimer s Disease Research Center (P50 AG05136) and the Adult Changes in Thought Study (U01 AG006781). Plasma samples were obtained from participants enrolled in the Pacific Udall Center Clinical Core which is supported by NIH grant P50 NS062684 and resources and the use of facilities at the Veterans Affairs Puget Sound System. Funding Information: This work was funded by grants from the National Institutes of Health (NIH) (R21 NS104511, R01 AG056711, and U01 NS091272 to J.Z. and M.S., and R21 MH118160 to J.Z. and T.S.) and grants from China (NSFC81671187 and 2016YFC1306502 to J.Z., for some of the validation studies). Autopsy materials used in this study were obtained from the University of Washington Neuropathology Core, which is supported by the Alzheimer{\textquoteright}s Disease Research Center (P50 AG05136) and the Adult Changes in Thought Study (U01 AG006781). Plasma samples were obtained from participants enrolled in the Pacific Udall Center Clinical Core which is supported by NIH grant P50 NS062684 and resources and the use of facilities at the Veterans Affairs Puget Sound System. Publisher Copyright: {\textcopyright} 2020 The Author(s).",
year = "2020",
month = jul,
day = "8",
doi = "10.1186/s40478-020-00983-w",
language = "English (US)",
volume = "8",
journal = "Acta neuropathologica communications",
issn = "2051-5960",
publisher = "BioMed Central",
number = "1",
}