Pyroptosis-mediator GSDMD promotes Parkinson's disease pathology via microglial activation and dopaminergic neuronal death

被引：6

作者：

Zhang, Xiaoshuang ^{[1
,2
]}

Zhang, Yunhe ^{[1
,2
]}

Wang, Boya ^{[1
,2
]}

Xie, Chuantong ^{[1
,2
]}

Wang, Jinghui ^{[1
,2
]}

Fang, Rong ^{[1
,2
]}

Dong, Hongtian ^{[1
,2
]}

Fan, Guangchun ^{[1
,2
]}

Wang, Mengze ^{[1
,2
]}

He, Yongtao ^{[1
,2
]}

Shen, Chenye ^{[1
,2
]}

Duan, Yufei ^{[1
,2
]}

Zhao, Jiayin ^{[1
,2
]}

Liu, Zhaolin ^{[1
,2
]}

Li, Qing ^{[1
,2
]}

Ma, Yuanyuan ^{[1
,2
]}

Yu, Mei ^{[1
,2
]}

Wang, Jian ^{[1
,2
]}

Fei, Jian ^{[3
,4
,5
]}

Xiao, Lei ^{[1
,2
,5
]}

Huang, Fang ^{[1
,2
,5
]}

机构：

[1] Fudan Univ, Jingan Dist Ctr Hosp Shanghai, Dept Translat Neurosci, State Key Lab Med Neurobiol, 138 Yixueyuan Rd, Shanghai 200032, Peoples R China

[2] Fudan Univ, Inst Brain Sci, MOE Frontiers Ctr Brain Sci, 138 Yixueyuan Rd, Shanghai 200032, Peoples R China

[3] Tongji Univ, Sch Life Sci & Technol, 1239 Siping Rd, Shanghai 200092, Peoples R China

[4] Shanghai Model Organisms Ctr Inc, Shanghai Engn Res Ctr Model Organisms, Shanghai 201203, Peoples R China

[5] Fudan Univ, Shanghai Med Coll, State Key Lab Med Neurobiol, 138 Yixueyuan Rd, Shanghai 200032, Peoples R China

来源：

BRAIN BEHAVIOR AND IMMUNITY | 2024年 / 119卷

基金：

中国国家自然科学基金;

关键词：

Parkinson's disease; GSDMD; Pyroptosis; Disulfiram; Dopaminergic neuron; Microglia; MPTP MOUSE MODEL; IN-VITRO MODEL; NLRP3; INFLAMMASOME; SUBSTANTIA-NIGRA; GASDERMIN-D; FLUORO-JADE; CELL-DEATH; SUPPRESSION; CASPASE-11; PROTECTS;

D O I：

10.1016/j.bbi.2024.03.038

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

GSDMD-mediated pyroptosis occurs in the nigrostriatal pathway in Parkinson's disease animals, yet the role of GSDMD in neuroinflammation and death of dopaminergic neurons in Parkinson's disease remains elusive. Here, our in vivo and in vitro studies demonstrated that GSDMD, as a pyroptosis executor, contributed to glial reaction and death of dopaminergic neurons across different Parkinson's disease models. The ablation of the Gsdmd attenuated Parkinson's disease damage by reducing dopaminergic neuronal death, microglial activation, and detrimental transformation. Disulfiram, an inhibitor blocking GSDMD pore formation, efficiently curtailed pyroptosis, thereby lessening the pathology of Parkinson's disease. Additionally, a modification in GSDMD was identified in the blood of Parkinson's disease patients in contrast to healthy subjects. Therefore, the detected alteration in GSDMD within the blood of Parkinson's disease patients and the protective impact of disulfiram could be promising for the diagnostic and therapeutic approaches against Parkinson's disease.

引用

页码：129 / 145

页数：17

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