Bioactive Selenium Peptides Rescue Dopaminergic Neurodegeneration via Coordinated Signal Remodeling and Redox Reinforcement

Abstract

Selenium-dependent antioxidant systems are critical for neuronal redox balance, but whether Parkinson’s disease (PD) involves systemic selenium deficiency or selective utilization impairment remains unclear. Using large-scale CSF and plasma proteomic datasets from the PPMI cohort, we show that PD is characterized by specific downregulation of secreted selenoprotein GPX3 in the CSF, indicating a functional selenium utilization disorder rather than global deficiency. To address this, we developed a selenium-modified bioactive peptide (IPP-Se) derived from Idesia polycarpa cake peptides. In a 6-OHDA-induced C. elegans PD model, IPP-Se robustly rescued locomotor deficits and restored dopamine-dependent behaviors. Mechanistically, IPP-Se exerts dual synergistic neuroprotection: it reactivates protein dephosphorylation and axon guidance pathways while activating GPX3-centered endogenous antioxidant networks. Our findings identify GPX3-centered selenium utilization failure as an underappreciated pathogenic feature of PD and establish IPP-Se as a promising precision intervention strategy.