Tenuigenin targets Trim31 and NF-κB pathway to protect dopaminergic neurons in Parkinson's disease mice

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the SN and the accumulation of α-synuclein (α-syn). In this study, we explored the neuroprotective effects of the natural compound tenuigenin on PD through bioinformatics analysis and in vivo experiments. We analyzed GEO datasets GSE99039 and GSE7307 and found that the expression of trim31 was significantly decreased in both peripheral blood and substantia nigra (SN) tissues of PD patients. Using a PD mouse model with overexpressed human α-syn in SN, we also discovered that tenuigenin treatment significantly reversed the downregulation of trim31. And the finding was further validated by quantitative proteomics, RT-qPCR, and Western blotting. Gene ontology (GO) enrichment analysis revealed that differentially expressed genes (DEGs) can enrich in the pathway of "positive regulation of NF-κB transcription factor activity." Tenuigenin treatment also effectively suppressed NF-κB upregulation in the SN of PD mice, reduced TNF-α expression and microglial activation, which suggesting that its neuroprotective effects may be mediated through inhibiting NF-κB-induced neuroinflammation. Additionally, tenuigenin exhibited significant protective effects on DA neurons. Our results indicate that tenuigenin targets trim31 as a key regulator and modulates the pathways of NF-κB to achieve anti-inflammatory and neuroprotective effects. Therefore, tenuigenin holds promise as a potential therapeutic candidate for PD.