Tristetraprolin attenuates microglial neuroinflammation via post-transcriptional destabilization of TRAF6 mRNA in Parkinson's disease.

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.