Negative regulation of TREM2-mediated C9orf72 poly-GA clearance by the NLRP3 inflammasome

Xiaoqiu Shu; Chen Wei; Wen-Yo Tu; Keke Zhong; Shuyuan Qi; Ailian Wang; Lei Bai; Shan-Xin Zhang; Benyan Luo; Zhen-Zhong Xu; Kejing Zhang; Chengyong Shen

Cell Reports (Feb 2023)

Negative regulation of TREM2-mediated C9orf72 poly-GA clearance by the NLRP3 inflammasome

Xiaoqiu Shu,
Chen Wei,
Wen-Yo Tu,
Keke Zhong,
Shuyuan Qi,
Ailian Wang,
Lei Bai,
Shan-Xin Zhang,
Benyan Luo,
Zhen-Zhong Xu,
Kejing Zhang,
Chengyong Shen

Affiliations

Xiaoqiu Shu: Department of Neurobiology of First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China
Chen Wei: Department of Neurobiology of First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China
Wen-Yo Tu: Department of Neurobiology of First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China
Keke Zhong: Department of Neurobiology of First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China
Shuyuan Qi: Department of Neurobiology of First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China
Ailian Wang: Department of Neurobiology of First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China
Lei Bai: Department of Neurobiology of First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China
Shan-Xin Zhang: School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University, Hangzhou 310058, China
Benyan Luo: Department of Neurobiology of First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China
Zhen-Zhong Xu: School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University, Hangzhou 310058, China
Kejing Zhang: Department of Neurobiology of First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China; Corresponding author
Chengyong Shen: Department of Neurobiology of First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University, Hangzhou 310058, China; Corresponding author

Journal volume & issue: Vol. 42, no. 2
p. 112133

Abstract

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Summary: Expansion of the hexanucleotide repeat GGGGCC in the C9orf72 gene is the most common genetic factor in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Poly-Gly-Ala (poly-GA), one form of dipeptide repeat proteins (DPRs) produced from GGGGCC repeats, tends to form neurotoxic protein aggregates. The C9orf72 GGGGCC repeats and microglial receptor TREM2 are both associated with risk for ALS/FTD. The role and regulation of TREM2 in C9orf72-ALS/FTD remain unclear. Here, we found that poly-GA proteins activate the microglial NLRP3 inflammasome to produce interleukin-1β (IL-1β), which promotes ADAM10-mediated TREM2 cleavage and inhibits phagocytosis of poly-GA. The inhibitor of the NLRP3 inflammasome, MCC950, reduces the TREM2 cleavage and poly-GA aggregates, resulting in the alleviation of motor deficits in poly-GA mice. Our study identifies a crosstalk between NLRP3 and TREM2 signaling, suggesting that targeting the NLRP3 inflammasome to sustain TREM2 is an approach to treat C9orf72-ALS/FTD.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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