TGM2 drives microglial senescence by inhibiting autophagy via the PI3K/AKT/mTORC1 pathway.

Zhiqiang Li, Yuxiang Tang, Dongyuan Zhang, Jiayi Li, Tianxiang Wang, Qiuxia Pan, Xianbin Meng, Xiaolin Tian, Haiteng Deng

CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China; Zhejiang Key Laboratory of Multiomics and Molecular Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing City, Zhejiang Province, 314006, China. Electronic address: [email protected]. · pubmed

Paper

Abstract

Microglial senescence is increasingly recognized as a driver of age-related neurodegeneration by impairing autophagic clearance and exacerbating neuroinflammation. However, the molecular mechanisms coupling senescence to autophagy dysfunction remain unclear. Here we identify transglutaminase 2 (TGM2) as a critical regulator linking these processes. We show that TGM2 is selectively upregulated in senescent microglia, where it assembles a previously unrecognized signaling complex with 14-3-3γ (YWHAG) and PI3K (p85α). This complex sustains AKT phosphorylation, constitutively activates mTORC1, and thereby inhibits autophagic flux. Pharmacological inhibition of TGM2 with cystamine dihydrochloride (CD) reduces this complex, restores autophagy, attenuates senescence-associated secretory phenotype (SASP) and reactive oxygen species (ROS) levels, and significantly reverses cognitive and motor deficits in aged mice. These findings support a model in which TGM2-related signaling is linked to microglial autophagy dysfunction and senescence, suggesting that targeting TGM2 may offer a novel therapeutic approach for age-related neurodegenerative disorders.

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Research summary

TGM2 drives microglial senescence by forming a complex with 14-3-3γ and PI3K to constitutively activate mTORC1, thereby inhibiting autophagy, and its inhibition reverses age-related cognitive and motor deficits in mice. This paper is relevant because it identifies a specific molecular mechanism (TGM2-mediated autophagy inhibition) that drives cellular senescence in the brain, offering a potential target for intervening in the root causes of age-related neurodegeneration rather than just treating symptoms.

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