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

doi:10.1016/j.celrep.2023.112133

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

Cell Rep. 2023 Feb 28;42(2):112133. doi: 10.1016/j.celrep.2023.112133. Epub 2023 Feb 16.

Authors

Affiliations

¹ 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.
² 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.
³ 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. Electronic address: kjzhang@zju.edu.cn.
⁴ 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. Electronic address: cshen@zju.edu.cn.

PMID: 36800288
DOI: 10.1016/j.celrep.2023.112133

Abstract

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.

Keywords: C9orf72; CP: Immunology; CP: Neuroscience; NLRP3; TREM2; amyotrophic lateral sclerosis; frontotemporal dementia; neuroinflammation; poly-Gly-Ala.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / metabolism
Animals
C9orf72 Protein / genetics
C9orf72 Protein / metabolism
DNA Repeat Expansion
Dipeptides / metabolism
Disease Models, Animal
Frontotemporal Dementia* / genetics
Inflammasomes
Mice
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
Proteins / genetics

Substances

C9orf72 Protein
C9orf72 protein, mouse
Dipeptides
Inflammasomes
N-glycylalanine
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Proteins
Trem2 protein, mouse