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Neurobiol Aging. 2015 Jul;36(7):2304-2318. doi: 10.1016/j.neurobiolaging.2015.03.015. Epub 2015 Apr 7.

P2X7 receptor is critical in α-synuclein--mediated microglial NADPH oxidase activation.

Author information

1
Department of Neurology & Institute of Neurology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2
Department of Pathology, University of Washington, Seattle, WA, USA.
3
Department of Neurology & Institute of Neurology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Neurology, Laboratory of Neurodegenerative Diseases, Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Science and Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: chen_sd@medmail.com.cn.
4
Department of Pathology, University of Washington, Seattle, WA, USA; Department of Pathology, Peking University Third Hospital/Institute of Basic Science, Peking University Health Science Center, Beijing, China. Electronic address: zhangpresent@gmail.com.

Abstract

Activated microglia are commonly observed in individuals with neurodegenerative disorders, including Parkinson's disease (PD) and are believed to contribute to neuronal death. This process occurs at least due partially to nicotinamide adenine dinucleotide phosphate oxidase (PHOX) activation, which leads to the production of superoxide and oxidative stress. α-Synuclein (α-Syn), a key protein implicated in PD pathogenesis, can activate microglia, contributing to death of dopaminergic neurons. Here, microglial cells (BV2) and primary cultured microglia were used to study the role that the purinergic receptor P2X7 plays in recognizing α-Syn and promoting PHOX activation. We demonstrate that both wild type and A53T mutant α-Syn readily activate PHOX, with the A53T form producing more rapid and sustained effects,that is, oxidative stress and cellular injuries. Furthermore, this process involves the activation of phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B) pathway. Thus, it is concluded that stimulation of the microglial P2X7 receptor by extracellular α-Syn, with PI3K/AKT activation and increased oxidative stress, could be an important mechanism and a potential therapeutic target for PD.

KEYWORDS:

Microglia; P2X7 receptor; PI3K/AKT signaling; Parkinson's disease; α-Synuclein

[Indexed for MEDLINE]

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