Selenoprotein W Mitigates 6‐ OHDA ‐Induced Dopaminergic Damage and Motor Dysfunction in Mice

ABSTRACT Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the loss of nigral dopaminergic neurons, often linked to oxidative stress and impaired cellular resilience. Selenoprotein W (SELENOW), known for its high selenium sensitivity and redox‐regulatory functions, has an unclear role in the PD‐related nigrostriatal pathway. In this study, we first observed that whole‐brain SELENOW knockout mice displayed increased vulnerability to 6‐hydroxydopamine (6‐OHDA)‐induced PD modeling. To investigate this further, we generated mice with dopaminergic neuron‐specific SELENOW knockout. While SELENOW deficiency in these neurons did not influence overall growth or baseline motor behaviors, it led to worsened motor dysfunction and increased loss of nigrostriatal dopaminergic neurons following unilateral intrastriatal 6‐OHDA injection. Moreover, we observed that SELENOW expression was downregulated under PD conditions. Mechanistically, this heightened susceptibility appeared linked to increased nigral oxidative stress, a weakened response of the antioxidant regulator NRF2, and diminished activation of the striatal AKT signaling pathway. In conclusion, the present study identifies SELENOW as an important modulator of dopaminergic neuron vulnerability to PD, likely through NRF2‐mediated redox and stress‐responsive signaling. These findings offer new insights into the role of selenoproteins in PD and suggest potential clues for therapeutic strategies.