CNS neuroscience & therapeutics · 2026
Neuroprotective Role of E3 Ubiquitin Ligase TRIM2 in Parkinson's Disease: Attenuation of Oxidative Stress and Apoptosis via Promoting ELAVL1 Ubiquitination.
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Liang Wei, Sun WenJie, Zhao ZhiJun, Song Ke, Jia JinYing
Аннотация
BACKGROUND: Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, where oxidative stress and neuronal apoptosis are key pathogenic events. In this study, we identified a downregulated TRIM2 in the substantia nigra pars compacta (SNc) of PD rats based on label-free proteomics. However, the impact of TRIM2 on PD is unknown.
METHODS: We used 6-hydroxydopamine (6-OHDA) to construct a PD model in vivo and in vitro.
RESULTS: TRIM2 overexpression alleviated neurobehavioral deficits, mitigated the loss of dopaminergic neurons, and suppressed oxidative stress and apoptosis in the SNc of PD rats. These effects were also observed in the 6-OHDA-treated differentiated BE (2)-M17 cells. Mechanistically, the RNA-binding protein ELAVL1 was identified as a critical downstream target, given that the database predicts it to be a TRIM2-interacted protein and a PD-related protein. Herein, TRIM2 directly interacted with ELAVL1 and promoted its ubiquitin-mediated degradation. Crucially, rescue experiments confirmed that the neuroprotection conferred by TRIM2 was counteracted by ELAVL1 overexpression in the 6-OHDA-treated BE (2)-M17 cells that exhibited neuronal-like properties.
CONCLUSION: Our findings uncovered a novel TRIM2-ELAVL1 axis as a pivotal regulatory mechanism in PD pathogenesis, positioning TRIM2 as a potential target for therapeutic intervention in PD.
METHODS: We used 6-hydroxydopamine (6-OHDA) to construct a PD model in vivo and in vitro.
RESULTS: TRIM2 overexpression alleviated neurobehavioral deficits, mitigated the loss of dopaminergic neurons, and suppressed oxidative stress and apoptosis in the SNc of PD rats. These effects were also observed in the 6-OHDA-treated differentiated BE (2)-M17 cells. Mechanistically, the RNA-binding protein ELAVL1 was identified as a critical downstream target, given that the database predicts it to be a TRIM2-interacted protein and a PD-related protein. Herein, TRIM2 directly interacted with ELAVL1 and promoted its ubiquitin-mediated degradation. Crucially, rescue experiments confirmed that the neuroprotection conferred by TRIM2 was counteracted by ELAVL1 overexpression in the 6-OHDA-treated BE (2)-M17 cells that exhibited neuronal-like properties.
CONCLUSION: Our findings uncovered a novel TRIM2-ELAVL1 axis as a pivotal regulatory mechanism in PD pathogenesis, positioning TRIM2 as a potential target for therapeutic intervention in PD.