Erythrocytic α-synuclein contained in microvesicles regulates astrocytic glutamate homeostasis: a new perspective on Parkinson's disease pathogenesis

Lifu Sheng, Tessandra Stewart, Dishun Yang, Eric Thorland, David Soltys, Patrick Aro, Tarek Khrisat, Zhiying Xie, Na Li, Zongran Liu, Chen Tian, Matthew Bercow, Junichi Matsumoto, Cyrus P. Zabetian, Elaine Peskind, Joseph F. Quinn, Min Shi, Jing Zhang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)102
Number of pages1
JournalActa Neuropathologica Communications
Volume8
Issue number1
DOIs
StatePublished - Jul 8 2020

Keywords

  • Alpha-synuclein
  • Astrocytes
  • Blood-brain barrier
  • Extracellular vesicles
  • Glutamate
  • Parkinson’s disease

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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  • Cite this

    Sheng, L., Stewart, T., Yang, D., Thorland, E., Soltys, D., Aro, P., Khrisat, T., Xie, Z., Li, N., Liu, Z., Tian, C., Bercow, M., Matsumoto, J., Zabetian, C. P., Peskind, E., Quinn, J. F., Shi, M., & Zhang, J. (2020). Erythrocytic α-synuclein contained in microvesicles regulates astrocytic glutamate homeostasis: a new perspective on Parkinson's disease pathogenesis. Acta Neuropathologica Communications, 8(1), 102. https://doi.org/10.1186/s40478-020-00983-w