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

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CELL REPORTS
卷 42, 期 2, 页码 -

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CELL PRESS
DOI: 10.1016/j.celrep.2023.112133

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Expansion of the GGGGCC repeat in the C9orf72 gene is the most common genetic factor in ALS and FTD. The produced poly-GA proteins tend to form neurotoxic aggregates. The relationship between C9orf72 and TREM2 in ALS/FTD is still unclear.
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 aggre-gates. 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 pro-teins activate the microglial NLRP3 inflammasome to produce interleukin-1b (IL-1b), which promotes ADAM10-mediated TREM2 cleavage and inhibits phagocytosis of poly-GA. The inhibitor of the NLRP3 inflam-masome, 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.

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