An oxidized ribonucleotide 8-oxoGTP drives neuroinflammation and accelerates cognitive decline.

Jin Li, Zhen-He Wang, Jia-Xin Pan, Zhe-Li Jiang, Rui Li, Xu-Fan Gao, Gang Sheng, Zi-Hui Wang, Ya-Qing Ma, Zheng-Lu Wang, Ting Wang, Ran Huan, Lv-Tao Zeng, Wei Zhang, Da-Peng Dai, Ju Cui, Xiao-Yang Zhou, Li-Qun Zhang, Wen Su, Hai-Bo Chen, Guo-Xin Hu, Ruo-Mei Qi, Jian-Ping Cai

Department of Basic Innovation Research, Beijing Hospital, National Center or Gerontology; National Clinical Research Center for Gerontology; The Key Laboratory of Geriatrics of NHC; Beijing Key Laboratory of Aging Mechanism and Intervention Research on Aging-Related Diseases; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.Department of Basic Innovation Research, Beijing Hospital, National Center or Gerontology; National Clinical Research Center for Gerontology; The Key Laboratory of Geriatrics of NHC; Beijing Key Laboratory of Aging Mechanism and Intervention Research on Aging-Related Diseases; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. · pubmed

Paper

Abstract

Oxidative stress is a hallmark of aging and a key driver of neurodegenerative diseases. While much attention has been given to oxidative damage of macromolecules, the functional consequences of oxidizing the abundant nucleotide triphosphate (NTP) pool remain largely unknown. Here, we identify oxidized GTP (8-oxoGTP)-a major product of NTP oxidation-not as a mere marker of damage, but as an endogenous signaling molecule that drives microglial activation and neuroinflammation. 8-oxoGTP accumulated in the aging mouse brain, and its elevation was sufficient to induce synaptic dysfunction, tau hyperphosphorylation, neuronal loss, and cognitive decline. Mechanistically, 8-oxoGTP functioned as a potent activator of heterotrimeric G proteins, binding more strongly to Gα subunits than GTP itself, triggering Src kinase/MAPK/Akt/NF-κB signaling in microglia, leading to pro-inflammatory cytokine production, reactive oxygen species generation, and neurotoxicity. Pharmacological inhibition of Src family kinases rescued the neuroinflammatory and cognitive phenotypes induced by 8-oxoGTP. Our findings reveal a previously unrecognized mechanism linking nucleotide oxidation to age-associated neurodegenerative processes.

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper claims that 8-oxoGTP acts as an endogenous signaling molecule that drives microglial activation and neuroinflammation, thereby accelerating cognitive decline. This is relevant to longevity research because it identifies a specific molecular mechanism linking oxidative stress (a root cause of aging) to neurodegeneration, offering a potential therapeutic target to mitigate age-related brain dysfunction rather than just treating downstream symptoms.

Author of this paper? Send a correction.