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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.

SUBMITTER: Sheng L

PROVIDER: S-EPMC7346449 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Sheng Lifu L Stewart Tessandra T Yang Dishun D Thorland Eric E Soltys David D Aro Patrick P Khrisat Tarek T Xie Zhiying Z Li Na N Liu Zongran Z Tian Chen C Bercow Matthew M Matsumoto Junichi J Zabetian Cyrus P CP Peskind Elaine E Quinn Joseph F JF Shi Min M Zhang Jing J

Acta neuropathologica communications 20200708 1

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 c ...[more]

PMID: 32641150

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Project description:BackgroundThe accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders.MethodsPrimary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism.ResultsThe number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877.ConclusionsPathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD.

Project description:BackgroundImmune system dysfunction, including higher levels of peripheral monocytes and inflammatory cytokines, is an important feature of Parkinson's disease (PD) pathogenesis, although the mechanism underlying the process remains to be investigated. In the central nervous system, it is well-known that α-synuclein (α-syn), a key protein involved in PD, activates microglia potently, and it is also reported that α-syn exists in the peripheral system, especially in erythrocytes or red blood cells (RBC) at exceedingly high concentration. The current study focused on the possibility that RBC-derived α-syn mediates the sensitization of peripheral monocytes in PD patients.MethodsThe hyperactivation of monocytes was assessed quantitatively by measuring mRNA levels of typical inflammatory cytokines (including IL-1β, IL-6 and TNF-α) and protein levels of secreted inflammatory cytokines (including pro-inflammatory cytokines: IL-1β, IL-6, TNF-α, IL-8, IFN-γ, IL-2, and IL-12p70 and anti-inflammatory cytokines: IL-4, IL-10, and IL-13). Western blot, nanoparticle tracking analysis and electron microscopy were used to characterize RBC-derived extracellular vesicles (RBC-EVs). Inhibitors of endocytosis and leucine-rich repeat kinase 2 (LRRK2), another key protein involved in PD, were used to investigate how these two factors mediated the process of monocyte sensitization by RBC-EVs.ResultsIncreased inflammatory sensitization of monocytes was observed in PD patients and PD model mice. We found that α-syn-containing RBC-EVs isolated from PD model mice or free form oligomeric α-syn induced the inflammatory sensitization of THP-1 cells, and demonstrated that endocytosis was a requirement for this pathophysiological pathway. Furthermore, the hyperactivation of THP-1 cells induced by RBC-EVs was associated with increased LRRK2 production and kinase activity. The phenomenon of inflammatory sensitization of human monocytes and increased LRRK2 were also observed by the treatment of RBC-EVs isolated from PD patients.ConclusionsOur data provided new insight into how hyperactivation of monocytes occurs in PD patients, and identified the central role played by α-syn-containing RBC-EVs in this process.

Dataset Information

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

Publications

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

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