Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction for which there is an unmet need for better treatment options. Although oxidative stress is a common feature of neurodegenerative diseases, notably PD, there is currently no efficient therapeutic strategy able to tackle this multi-target pathophysiological process. Based on our previous observations of the potent antioxidant and neuroprotective activity of SELENOT, a vital thioredoxin-like selenoprotein, we designed the small peptide PSELT from its redox active site to evaluate its antioxidant properties in vivo, and its potential polyfunctional activity in PD models. PSELT protects neurotoxin-treated dopaminergic neurons against oxidative stress and cell death, and their fibers against neurotoxic degeneration. PSELT is cell-permeable and acts in multiple subcellular compartments of dopaminergic neurons that are vulnerable to oxidative stress. In rodent models of PD, this protective activity prevented neurodegeneration, restored phosphorylated tyrosine hydroxylase levels, and led to improved motor skills. Transcriptomic analysis revealed that gene regulation by PSELT after MPP⁺ treatment negatively correlates with that occurring in PD, and positively correlates with that occurring after resveratrol treatment. Mechanistically, a major impact of PSELT is via nuclear stimulation of the transcription factor EZH2, leading to neuroprotection. Overall, these findings demonstrate the potential of PSELT as a therapeutic candidate for treatment of PD, targeting oxidative stress at multiple intracellular levels.

帕金森氏病（PD）是一种以运动功能障碍为特征的神经退行性疾病，目前尚无更好的治疗选择。尽管氧化应激是神经退行性疾病（尤其是PD）的常见特征，但目前尚无有效的治疗策略能够解决这种多目标病理生理过程。根据我们先前对SELENOT（一种重要的硫氧还蛋白样硒蛋白）有效的抗氧化和神经保护活性的观察结果，我们从其氧化还原活性位点设计了小肽PSELT，以评估其体内抗氧化性能，及其在PD模型中的潜在多功能活性。PSELT保护神经毒素治疗的多巴胺能神经元免受氧化应激和细胞死亡，并保护其纤维免受神经毒性变性。PSELT具有细胞渗透性，并在易受氧化应激影响的多巴胺能神经元的多个亚细胞区室中起作用。在PD的啮齿动物模型中，这种保护活性可防止神经变性，恢复磷酸化酪氨酸羟化酶水平并改善运动技能。转录组学分析显示，MPP ⁺后，PSELT基因调控治疗与PD中发生的负相关，与白藜芦醇治疗后发生的正相关。从机理上讲，PSELT的主要影响是通过核转录因子EZH2的核刺激，从而导致神经保护。总体而言，这些发现证明了PSELT作为治疗PD的潜在疗法的潜力，其靶向多个细胞内水平的氧化应激。