The neuroprotective effect of tetrahydrobiopterin

四氢生物蝶呤的神经保护作用

• 批准号: 7220615
• 负责人: Un Jung Kang
• 金额: $ 32.69万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7220615
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenylpyridinium; 14p; Accounting; Aging; Antioxidants; Apoptosis; Attenuated; Bioenergetics; Brain; Buthionine Sulfoximine; Cell Death; Cell Death Signaling Process; Cell Line; Cell Survival; Cessation of life; Characteristics; Chronic; Compatible; Complement; Conflict (Psychology); Corpus striatum structure; Data; Disease model; Disruption; Dopamine; Dopaminergic Cell; Electron Transport; Enzymes; Etiology; Exposure to; Fibroblasts; Figs - dietary; Fluorescence; GTP Cyclohydrolase; Generations; Glutamates; Glutathione; In Vitro; Incidence; Individual; Injection of therapeutic agent; Life; Measurement; Mediating; Membrane; Membrane Potentials; Mitochondria; Modeling; Mus; Neurons; Nitric Oxide; Nitric Oxide Synthase; Numbers; Oxidative Phosphorylation; Oxidative Stress; Paraquat; Parkinson Disease; Pathogenesis; Pathway interactions; Peroxides; Physiological; Production; Reactive Oxygen Species; Reduced Glutathione; Research Personnel; Resistance; Respiration; Role; Rotenone; Signal Transduction; Slice; Substantia nigra structure; Sulfhydryl Compounds; Superoxides; System; Testing; Thioredoxin; Toxic effect; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; adeno-associated viral vector; buthionine; cofactor; cytochrome c; dopaminergic neuron; in vivo; in vivo Model; inhibitor/antagonist; mitochondrial dysfunction; mitochondrial membrane; mouse model; neuron loss; neuronal survival; oxidation; pars compacta; prevent; programs; tetrahydrobiopterin

DESCRIPTION (provided by applicant): While multiple etiologies are likely to account for Parkinson's disease (PD), the core pathogenic feature is degeneration of dopaminergic neurons, particularly those in the substantia nigra pars compacta (SNpc), with shared common final pathways involving oxidative damage, mitochondrial dysfunction, or both. Therefore, one may hypothesize that dopaminergic neurons in the SNpc are selectively vulnerable to oxidative stresses and/or mitochondrial disruption and understanding the mechanism of this selectivity may reveal the pathogenesis. However, our data show that ventral mesencephalic dopaminergic neurons in culture have an enhanced antioxidant capacity, as they are better able to resist oxidative stresses such as glutathione depletion and peroxide treatment than nondopaminergic neurons. In addition, their enhanced antioxidant capacity is reflected in lower reactive oxygen species (ROS) and higher reduced glutathione levels than nondopaminergic neurons. We hypothesize that an enhanced antioxidant capacity is essential for the survival of dopaminergic neurons that may be subjected to increased oxidative stress exerted by dopamine and its metabolites. We postulate that disruption of this innate antioxidant capacity makes them vulnerable to additional environmental insults and thereby leads to selective degeneration. We noted that the enhanced antioxidant capacity in ventral mesencephalic dopaminergic neurons is due to tetrahydrobiopterin (BH4), which is the cofactor for tyrosine hydroxylase, the enzyme producing dopamine, but also lowers superoxide levels, partly be direct scavenging effect and modulates mitochondrial function. First, We will study the effect of BH4 on mitochondrial bioenergetics and function including initiation of death pathways. Second, we will examine the role of BH4 on NO and superoxide generation and in modulating other endogenous antioxidant systems. Third, the neuroprotective function of BH4 against PD models such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone toxicity, and glutathione depletion will be tested in vivo and in organotypic slice cultures, using hph-1 mice that are deficient in BH4, production.

描述（由申请人提供）：虽然多种病因可能是帕金森病（PD）的原因，但核心致病特征是多巴胺能神经元变性，特别是黑质丘脑部（SNpc）中的多巴胺能神经元变性，具有共同的最终通路，涉及氧化损伤、线粒体功能障碍或两者兼而有之。因此，可以假设SNpc中的多巴胺能神经元选择性地易受氧化应激和/或线粒体破坏的影响，并且理解这种选择性的机制可以揭示发病机制。然而，我们的数据表明，腹侧中脑多巴胺能神经元在文化中具有增强的抗氧化能力，因为它们能够更好地抵抗氧化应激，如谷胱甘肽耗竭和过氧化物处理比nondopaminergic神经元。此外，它们增强的抗氧化能力反映在较低的活性氧（ROS）和较高的还原型谷胱甘肽水平比非多巴胺能神经元。我们推测，增强的抗氧化能力是必不可少的多巴胺能神经元的生存，可能会受到多巴胺及其代谢产物产生的氧化应激增加。我们假设，这种先天的抗氧化能力的破坏，使他们容易受到额外的环境侮辱，从而导致选择性退化。我们注意到，腹侧中脑多巴胺能神经元的抗氧化能力增强是由于四氢生物蝶呤（BH 4），这是酪氨酸羟化酶，产生多巴胺的酶的辅因子，但也降低超氧化物水平，部分是直接清除作用和调节线粒体功能。首先，我们将研究BH 4对线粒体生物能量学和功能的影响，包括启动死亡途径。其次，我们将研究BH 4对NO和超氧化物生成以及调节其他内源性抗氧化系统的作用。第三，BH 4对PD模型如1-甲基-4-苯基-1，2，3，6-四氢吡啶、鱼藤酮毒性和谷胱甘肽耗竭的神经保护功能将在体内和器官型切片培养中使用BH 4产生缺陷的hph-1小鼠进行测试。

项目成果

Characterization of PINK1 processing, stability, and subcellular localization.

• DOI: 10.1111/j.1471-4159.2008.05398.x
• 发表时间: 2008-07
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Lin W;Kang UJ
• 通讯作者: Kang UJ

Paraquat induces dopaminergic dysfunction and proteasome impairment in DJ-1-deficient mice.

• DOI: 10.1093/hmg/ddm249
• 发表时间: 2007-12
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Wonsuk Yang;Linan Chen;Yunmin Ding;X. Zhuang;U. Kang