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

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

doi:10.1186/s40478-020-00983-w

Cited by 31 publications

(36 citation statements)

References 104 publications

(170 reference statements)

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“…Together, these cells form the neurovascular unit and their intercellular exchange is mandatory for BBB integrity and function (112). Studies directly addressing the mechanism of EV-crossing over the endothelial cell layer of the BBB suggested that the EV-transport mechanism is energydependent and can follow dynamin-, clathrin-, and caveolin-mediated as well as macropinocytic transcellular routes rather than paracellular diffusion (126)(127)(128)(129). Additionally, it was shown that uptake of blood-derived EVs by BMECS is, at least in part, mediated by transferrin receptormediated endocytosis (128).…”

Section: Accepted Articlementioning

confidence: 99%

Extracellular Vesicles in neural cell interaction and CNS homeostasis

et al. 2021

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Central nervous system (CNS) homeostasis critically depends on the interaction between neurons and glia cells. Extracellular vesicles (EVs) recently emerged as versatile messengers in CNS cell communication. EVs are released by neurons and glia in activity-dependent manner and address multiple target cells within and outside the nervous system. Here, we summarize the recent advances in understanding the physiological roles of EVs in the nervous system and their ability to deliver signals across the CNS barriers. In addition to the disposal of cellular components via EVs and clearance by phagocytic cells, EVs are involved in plasticity-associated processes, mediate trophic support and neuroprotection, promote axonal maintenance, and modulate neuroinflammation. While individual functional components of the EV cargo are becoming progressively identified, the role of neural EVs as compound multimodal signaling entities remains to be elucidated. Novel transgenic models and imaging technologies allow EVtracking in vivo and provide further insight into EV targeting and their mode of action. Overall, EVs represent key players in the maintenance of CNS homeostasis essential for the life-long performance of neural networks and thus provide a wide spectrum of biomedical applications.

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Section: Accepted Articlementioning

confidence: 99%

Extracellular Vesicles in neural cell interaction and CNS homeostasis

et al. 2021

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“…alpha-Synuclein has been reported to trigger the opening of connexin 43 (Cx43) hemichannels and pannexin-1 (Panx1) channels in mouse cortical astrocytes, leading to alterations in [Ca 2+ ] i levels, production of nitric oxide (NO), enhanced purinergic and glutamatergic signaling, altered mitochondrial morphology and reduced astrocyte survival [ 599 ]. Another recently published study suggests that vesicle-associated aSyn, deriving from erythrocytes, effectively crosses the BBB and accumulates within astrocytes, impairing glutamate uptake, probably due to interactions of oligomeric aSyn with excitatory amino acid transporter 2 (EAAT2) [ 600 ]. Furthermore, astrocytes overexpressing mutant A35T and A30P aSyn triggered ER stress and damaged the Golgi apparatus, finally leading to apoptotic cell death [ 601 ].…”

Section: Glia In the Cns: Scavengers Of Extracellular Asynmentioning

confidence: 99%

Neurons and Glia Interplay in α-Synucleinopathies

Mavroeidi

Xilouri

2021

IJMS

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Accumulation of the neuronal presynaptic protein alpha-synuclein within proteinaceous inclusions represents the key histophathological hallmark of a spectrum of neurodegenerative disorders, referred to by the umbrella term a-synucleinopathies. Even though alpha-synuclein is expressed predominantly in neurons, pathological aggregates of the protein are also found in the glial cells of the brain. In Parkinson’s disease and dementia with Lewy bodies, alpha-synuclein accumulates mainly in neurons forming the Lewy bodies and Lewy neurites, whereas in multiple system atrophy, the protein aggregates mostly in the glial cytoplasmic inclusions within oligodendrocytes. In addition, astrogliosis and microgliosis are found in the synucleinopathy brains, whereas both astrocytes and microglia internalize alpha-synuclein and contribute to the spread of pathology. The mechanisms underlying the pathological accumulation of alpha-synuclein in glial cells that under physiological conditions express low to non-detectable levels of the protein are an area of intense research. Undoubtedly, the presence of aggregated alpha-synuclein can disrupt glial function in general and can contribute to neurodegeneration through numerous pathways. Herein, we summarize the current knowledge on the role of alpha-synuclein in both neurons and glia, highlighting the contribution of the neuron-glia connectome in the disease initiation and progression, which may represent potential therapeutic target for a-synucleinopathies.

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“…In fact, the α-synuclein-induced opening of hemichannels and pannexons resulted in alterations in Ca 2+ dynamics, NO production, gliotransmitter release, mitochondrial morphology, and astrocyte survival. Recently, Sheng et al [142] provided a new perspective on the pathogenesis of PD; erythrocyte-derived α-synuclein in extracellular vesicles was found to readily cross the BBB and accumulate in astrocyte end-feet, where they impaired glutamate uptake, likely via interaction between EAAT2 and oligomeric α-synuclein.…”

Section: α-Synuclein Toxicitymentioning

confidence: 99%

Neuron-Astrocyte Interactions in Parkinson’s Disease

Miyazaki

Asanuma

2020

Cells

104

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Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.

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

Cited by 31 publications

References 104 publications

Extracellular Vesicles in neural cell interaction and CNS homeostasis

Extracellular Vesicles in neural cell interaction and CNS homeostasis

Neurons and Glia Interplay in α-Synucleinopathies

Neuron-Astrocyte Interactions in Parkinson’s Disease

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