A Role of hUCP2 in Mitochondrial Quality Control and Dopaminergic Neuroprotection

hUCP2 在线粒体质量控制和多巴胺能神经保护中的作用

• 批准号: 8739993
• 负责人: PING ZHANG
• 金额: $ 32.3万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8739993
• 关键词: 1-Methyl-4-phenylpyridinium; 5' -AMP-activated protein kinase; Affect; Age; Alleles; Apoptosis; Attenuated; Autophagocytosis; Bioenergetics; Brain; Brain Death; Cell Survival; Cells; Cessation of life; Defect; Disease model; Dopamine; Drosophila genus; Etiology; Functional disorder; Genetic; Glycine decarboxylase; Head; Health; Human; Measures; Mediating; Mitochondria; Modeling; Morphology; Movement Disorders; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathway interactions; Phenocopy; Phosphorylation; Play; Population; Quality Control; Recombinants; Reporting; Resistance; Role; Rotenone; Structure; Substantia nigra structure; System; Testing; Toxic effect; Toxin; UCP2 protein; dopaminergic neuron; effective therapy; fly; loss of function; mitochondrial autophagy; neuron loss; neuroprotection; novel; pars compacta; protective effect; public health relevance; receptor; sensor; therapeutic target

DESCRIPTION (provided by applicant): Parkinson's disease (PD), caused by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta, is the most common movement disorder affecting 1% of the population over the age 60 with no cure or effective treatment. Although the etiology of PD remains unknown, converging evidence from genetic and toxin models points to dysregulation of mitochondrial remodeling and turnover as prominent cellular defects in PD pathophysiology. We recently reported that hucp2 expression in Drosophila DA neurons protects flies against rotenone-induced DA neuron death and head dopamine depletion. We have expanded our toxin model and demonstrated hUCP2 protective effect against MPP+-induced DA neuron degeneration. To begin to understand the protective mechanisms, we considered the bioenergetic consequences of mitochondrial uncoupling and postulated AMP activated protein kinase (AMPK) as a downstream effector of hUCP2. In supporting this idea, we detected phosphorylated AMPK¿ indicative of its activation when hucp2 expression is induced in Drosophila S2R+ cells. Consistent with our genetic interaction study revealing functional cooperation between hUCP2 and mitochondrial fusion molecules, our current results suggest hUCP2 neuroprotective effect requires mitochondrial fusion. Furthermore, increased autophagic activity is associated with hucp2 expression in brain DA neurons. Additional support for our proposed hUCP2-AMPK axis are results showing that toxin-induced mitochondrial fragmentation is attenuated in hucp2 or AMPK expressing primary DA neurons and AMPK protective effect against toxin-induced neuron loss is associated with less accumulation of the autophagy receptor Ref(2)P. Taken together, those preliminary results led us to hypothesize that activation of AMPK as the result of hucp2 expression promotes mitochondrial fusion and autophagy to enhance mitochondrial health and survival of DA neurons. To test our hypothesis, we will determine i) whether AMPK is a downstream effector of hUCP2 in regulating mitochondrial fusion/fission in DA neurons, ii) whether AMPK stimulates autophagic activity and mitochondrial turnover in DA neurons exposed to toxin and iii) whether mitochondrial fusion and autophagy are critical components in hUCP2-AMPK mediated DA neuron survival against toxin.

描述（由申请人提供）：帕金森病（PD）由黑质丘脑部多巴胺能（DA）神经元的选择性丧失引起，是最常见的运动障碍，影响1%的60岁以上人群，无法治愈或有效治疗。虽然PD的病因仍然未知，但来自遗传和毒素模型的汇聚证据指出线粒体重塑和周转失调是PD病理生理学中的突出细胞缺陷。 我们最近报道，hucp 2在果蝇DA神经元的表达保护苍蝇对鱼藤酮诱导的DA神经元死亡和头部多巴胺耗竭。我们已经扩展了我们的毒素模型，并证明了hUCP 2对MPP+诱导的DA神经元变性的保护作用。为了开始理解保护机制，我们考虑了线粒体解偶联的生物能量后果，并假设AMP活化蛋白激酶（AMPK）为hUCP 2的下游效应子。为了支持这一观点，我们检测到磷酸化AMPK？，这表明在果蝇S2 R+细胞中诱导hucp 2表达时AMPK？被激活。与我们揭示hUCP 2和线粒体融合分子之间的功能合作的遗传相互作用研究一致，我们目前的结果表明hUCP 2神经保护作用需要线粒体融合。此外，增加的自噬活性与脑DA神经元中的hucp 2表达相关。对我们提出的hUCP 2-AMPK轴的额外支持是显示毒素诱导的线粒体片段化在表达hucp 2或AMPK的原代DA神经元中减弱的结果，并且AMPK对毒素诱导的神经元损失的保护作用与自噬受体Ref（2）P的较少积累相关。这些初步结果使我们推测，作为hucp 2表达结果的AMPK活化促进线粒体融合和自噬，从而增强线粒体健康和存活DA神经元 为了检验我们的假设，我们将确定i）AMPK是否是hUCP 2在调节DA神经元中的线粒体融合/分裂中的下游效应物，ii）AMPK是否刺激暴露于毒素的DA神经元中的自噬活性和线粒体更新，以及iii）线粒体融合和自噬是否是hUCP 2-AMPK介导的DA神经元针对毒素的存活中的关键组分。