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

Author information

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.
      Authors
    • Shu X 1
    • Wei C 1
    • Tu WY 1
    • Zhong K 1
    • Qi S 1
    • Wang A 1
    • Bai L 1
    • Luo B 1
    • Zhang K 1
    (9 authors)
  • 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.
      Authors
    • Zhang SX 2
    • Xu ZZ 2
    (2 authors)
  • 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; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University, Hangzhou 310058, China.
      Authors
    • Shen C 3
    (1 author)

Cell Reports, 16 Feb 2023, 42(2):112133
https://doi.org/10.1016/j.celrep.2023.112133 PMID: 36800288 

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.

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Read article at publisher's site: https://doi.org/10.1016/j.celrep.2023.112133

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    Funding 

    Funders who supported this work.

    National Key Research and Development Program of China (2)

    • Grant ID: 2021YFA1101100

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    • Grant ID: 2022YFF1000500

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    National Natural Science Foundation of China (4)

    • Grant ID: 82230038

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    • Grant ID: 32071032

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    • Grant ID: 31871203

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    • Grant ID: 32271031

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    Natural Science Foundation of Zhejiang Province (1)

    • Grant ID: LZ22C110002

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