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.
Highlights
Parkinson’s disease is a neurodegenerative disorder characterized by both motor and nonmotor symptoms [40, 82]
Our previous study demonstrated that α-syn-carrying Red blood cell (RBC)-Extracellular vesicle (EV) enter the brain in wild type (WT) mice under conditions of LPS-induced blood–brain barrier (BBB) disruption [53]
Using Nanoparticle Tracking Analysis (NTA), we confirmed that the anti-CD235a immunocaptured RBC-EVs from human control and Parkinson’s disease plasma displayed a similar size distribution as those obtained from cultured RBCs in our previous study [53] (Supplemental Figure 1a-c)
Summary
Parkinson’s disease is a neurodegenerative disorder characterized by both motor and nonmotor symptoms [40, 82]. Its major pathological hallmark is the accumulation of insoluble α-synuclein (α-syn) in deposits known as Lewy bodies. One potential link may be glutamate homeostasis, a process that is under astrocytic control, and which has profound implications for neuronal survival. Astrocytes play a major role in communication between the cells of the BBB and neurons, and BBB dysfunction is well-known to accompany Parkinson’s disease and other neurodegenerative diseases [23, 29, 42, 91]. The links between astrocyte dysfunction and pathological α-syn are not entirely clear, and astrocytes express much less α-syn than neurons [56], they can contain α-synpositive inclusions in Parkinson’s disease [12], including in their processes [67, 87]. The source(s) of this astrocytic α-syn is not well-understood
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