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

昼夜节律蛋白Nocturnin在调节黑质多巴胺能神经元氧化应激中的作用

• 批准号: 10066683
• 负责人: Carla B. Green
• 金额: $ 45.04万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066683
• 关键词: Adenine; Cell Cycle; Cell Death; Cell Line; Cell physiology; Cells; Circadian Rhythms; Clock protein; Data; Disease; Disease model; Dopaminergic Cell; Enzymes; Event; Excessive Daytime Sleepiness; Excision; Exhibits; Link; Messenger RNA; Midbrain structure; Movement Disorders; Mus; NAD+ kinase; NADP; Neurodegenerative Disorders; Neurons; Oxidative Stress; Oxides; Parkinson Disease; Pathogenesis; Patients; Play; Poly A; Poly(A) Tail; Process; Protein Family; Proteins; Regulation; Reporting; Role; Sleep; Sleep Wake Cycle; Stress; Substantia nigra structure; Work; alpha synuclein; biological adaptation to stress; cell injury; circadian; circadian pacemaker; disease phenotype; dopaminergic neuron; inorganic phosphate; neuron loss; neuropathology; nocturnin; overexpression; prevent; protective effect; protein aggregation; response

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.

抽象的 帕金森病 (PD) 是第二常见的神经退行性疾病， 其特征是由于选择性丧失多巴胺而导致的严重运动障碍 中脑黑质神经元除了运动障碍外， PD 最常见的非运动表现是睡眠-觉醒周期的严重破坏， 约 80% 的患者表现出白天过度嗜睡或睡眠时间改变 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损伤导致a-的毒性聚集 尽管现有的数据很难解释突触核蛋白和氧化应激的增加。 确定氧化应激或蛋白质聚集是否是起始事件，这两个 过程明显相互影响，越来越多的证据表明氧化应激 至少参与导致神经病理学的细胞损伤的传播 在这个探索性应用中，我们将探讨昼夜节律蛋白 Nocturnin 在中的作用。 我们的数据表明，Nocturnin 是氧化的重要调节剂。 压力，较高的水平会加剧压力，较低的水平会提供保护作用。 据报道，帕金森病患者的黑质中夜曲蛋白表达上调，这表明 它可能在过度氧化应激反应中发挥作用，从而导致 发病机制，我们将通过细胞和小鼠的机械工作来检查这种联系 目前还没有任何治疗方法可以预防帕金森病中的神经细胞损失。 其次，通过抑制夜曲素来减少氧化应激可能会打破 细胞死亡的循环。