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

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.