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

被引：92

作者：

Jiang, Tianfang ^{[1
,2
]}

Hoekstra, Jake ^{[3
]}

Heng, Xin ^{[1
,2
]}

Kang, Wenyan ^{[1
,2
]}

Ding, Jianqing ^{[1
,2
]}

Liu, Jun ^{[1
,2
]}

Chen, Shengdi ^{[1
,2
,4
,5
]}

Zhang, Jing ^{[3
,6
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, Dept Neurol, Shanghai 200025, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, Inst Neurol, Shanghai 200025, Peoples R China

[3] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

[4] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Dept Neurol,Lab Neurodegenerat Dis, Shanghai, Peoples R China

[5] Shanghai Jiao Tong Univ, Sch Med, Shanghai 200025, Peoples R China

[6] Peking Univ, Hlth Sci Ctr, Hosp 3, Dept Pathol,Inst Basic Sci, Beijing 100871, Peoples R China

来源：

NEUROBIOLOGY OF AGING | 2015年 / 36卷 / 07期

基金：

美国国家卫生研究院;

关键词：

Parkinson's disease; Microglia; alpha-Synuclein; P2X7; receptor; PI3K/AKT signaling; OXIDATIVE STRESS; PARKINSONS-DISEASE; INDUCE APOPTOSIS; P2X(7) RECEPTOR; CELLS; MODEL; EXPRESSION; PHENOTYPE; PROTEINS; NEURODEGENERATION;

D O I：

10.1016/j.neurobiolaging.2015.03.015

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

03 ; 0303 ; 100203 ;

摘要：

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. alpha-Synuclein (alpha-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 alpha-Syn and promoting PHOX activation. We demonstrate that both wild type and A53T mutant alpha-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 a-Syn, with PI3K/AKT activation and increased oxidative stress, could be an important mechanism and a potential therapeutic target for PD. (C) 2015 Elsevier Inc. All rights reserved.

引用

页码：2304 / 2318

页数：15

共 53 条

[1] Reactive oxygen species induce apoptosis in bronchial epithelial BEAS-2B cells by inhibiting the antiglycation glyoxalase I defence: involvement of superoxide anion, hydrogen peroxide and NF-κB [J].