Role of the circadian protein Nocturnin in modulating oxidative stress in substantia nigra dopaminergic neurons

摘要 帕金森病(PD)是第二常见的神经退行性疾病，是 以选择性多巴胺丢失导致的严重运动障碍为特征的 来自中脑黑质的神经元。除了运动障碍， 帕金森病最常见的非运动性表现是睡眠-觉醒周期的主要中断， 约80%的患者表现出白天过度嗜睡或睡眠时间改变，以及 昼夜节律幅度降低。选择性多巴胺能细胞死亡的原因尚不清楚 但似乎是通过各种细胞侮辱导致a- 突触核蛋白和氧化应激增加。尽管现有的数据很难 确定氧化应激或蛋白质聚集是启动事件，这两个 这些过程显然是相互影响的，越来越多的证据表明氧化应激 至少参与了导致神经病理的细胞损伤的传播 警察。在这个探索性的应用中，我们将探索昼夜节律蛋白Nocturin在 帕金森病的发病机制。我们的数据表明，夜转素是一种重要的氧化调节剂 压力，较高的水平加剧压力，较低的水平提供保护作用。 据报道，帕金森病患者黑质中的夜翻素表达上调，提示 它可能在过度的氧化应激反应中发挥作用 发病机制，我们将通过在细胞和小鼠中的机制工作来检查这一联系 这项提议。目前还没有预防帕金森病和WE患者神经细胞丢失的治疗方法 假设通过抑制夜曲灵来减少氧化应激可能会打破 细胞死亡的循环。

Abstract Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by severe movement disorders that result from selective loss of dopamine neurons from the substantia nigra in the midbrain. In addition to the movement disorders, the most common non-motor manifestation of PD is a major disruption in sleep-wake cycles, with ~80% of patients exhibiting excessive daytime sleepiness or changes in sleep timing and reduced circadian amplitudes. The cause of the selective dopaminergic cell death is not known but appears to be through various cellular insults that result in toxic aggregation of the a- synuclein protein and increased oxidative stress. Although the existing data make difficult to determine whether oxidative stress or protein aggregation is the initiating event, these two processes clearly impact each other, and a growing body of evidence implicates oxidative stress as being involved in at least the propagation of cellular injury that leads to neuropathology in PD. In this exploratory application, we will explore the role of the circadian protein Nocturnin in the pathogenesis of PD. Our data suggest that Nocturnin is an important modulator of oxidative stress, with higher levels exacerbating stress and lower levels providing protective effects. Nocturnin has been reported to be upregulated in the substantia nigra in PD patients suggesting that it may be playing a role in excessive oxidative stress responses that contribute to pathogenesis and we will examine this link through mechanistic work in both cells and mice in this proposal. There are currently no treatments that prevent neuronal cell loss in PD and we hypothesize that reduction of oxidative stress through the inhibition of Nocturnin might break the cycle of cell death.