Experimental neurology · 2026
Tristetraprolin attenuates microglial neuroinflammation via post-transcriptional destabilization of TRAF6 mRNA in Parkinson's disease.
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Liu Xingwu, Min Xudong, Zhang Zhongfei, Du Zhuolin, Wei Jirui, Mao Hengxu, Zhang Shizhong, He Xiaozheng, Sun Xiang
Аннотация
BACKGROUND: Microglia-driven neuroinflammation is a central pathological hallmark of Parkinson's disease. Tristetraprolin (TTP), an RNA-binding protein, suppresses inflammation through facilitating the degradation of target mRNAs. However, its specific role in microglial activation during Parkinson's pathogenesis remains poorly characterized.
METHODS: Transcriptomic analysis was performed to identify the differentially expressed genes in A53T α-synuclein transgenic mice. TTP expression and function were assessed in vitro and in vivo. Mechanistic studies employed RNA immunoprecipitation, dual-luciferase reporter assays, and mRNA stability analyses. Therapeutic efficacy was evaluated using the NF-κB inhibitor dimethylamino parthenolide (DMAPT) in conjunction with behavioral assessments.
RESULTS: Transcriptomic analysis revealed significant upregulation of TTP in A53T mice, accompanied by enrichment of neuroinflammatory pathways. Immunofluorescence analysis identified that increased TTP expression was mainly detected in IBA1-positive microglia. Functionally, TTP knockdown enhanced pro-inflammatory cytokine production and exacerbated primary neuronal apoptosis. Mechanistically, TTP directly bound to the 3'-untranslated region (3'UTR) of TRAF6 mRNA, accelerating its degradation and thereby suppressing TRAF6/NF-κB signaling. In vivo, TTP knockdown enhanced neuroinflammation and aggravated dopaminergic neuron loss. Pharmacological inhibition of NF-κB by DMAPT attenuated microglial activation, preserved dopaminergic neurons, and ameliorated behavioral deficits.
CONCLUSIONS: TTP mitigated microglial neuroinflammation by promoting TRAF6 mRNA degradation and suppressing NF-κB signaling. Targeting NF-κB with DMAPT may represent a promising druggable strategy.
METHODS: Transcriptomic analysis was performed to identify the differentially expressed genes in A53T α-synuclein transgenic mice. TTP expression and function were assessed in vitro and in vivo. Mechanistic studies employed RNA immunoprecipitation, dual-luciferase reporter assays, and mRNA stability analyses. Therapeutic efficacy was evaluated using the NF-κB inhibitor dimethylamino parthenolide (DMAPT) in conjunction with behavioral assessments.
RESULTS: Transcriptomic analysis revealed significant upregulation of TTP in A53T mice, accompanied by enrichment of neuroinflammatory pathways. Immunofluorescence analysis identified that increased TTP expression was mainly detected in IBA1-positive microglia. Functionally, TTP knockdown enhanced pro-inflammatory cytokine production and exacerbated primary neuronal apoptosis. Mechanistically, TTP directly bound to the 3'-untranslated region (3'UTR) of TRAF6 mRNA, accelerating its degradation and thereby suppressing TRAF6/NF-κB signaling. In vivo, TTP knockdown enhanced neuroinflammation and aggravated dopaminergic neuron loss. Pharmacological inhibition of NF-κB by DMAPT attenuated microglial activation, preserved dopaminergic neurons, and ameliorated behavioral deficits.
CONCLUSIONS: TTP mitigated microglial neuroinflammation by promoting TRAF6 mRNA degradation and suppressing NF-κB signaling. Targeting NF-κB with DMAPT may represent a promising druggable strategy.