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

基本信息

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
项目类别：
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&apos -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

项目摘要

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（由适用提供）：帕金森氏病（PD），是由底苯二甲酸骨中多巴胺能（DA）神经元的选择性丧失引起的，是最常见的运动障碍，影响了60岁人口中1％的人口，没有治愈或有效治疗。尽管PD的病因仍然未知，但遗传和毒素模型的融合证据表明，线粒体重塑和周转的失调是PD病理生理学中明显的细胞缺陷。我们最近报道，果蝇DA神经元中的HUCP2表达可保护果蝇诱导的DA神经元死亡和头部多巴胺耗竭。我们已经扩展了毒素模型，并证明了针对MPP+诱导的DA神经元变性的HUCP2保护作用。为了开始理解受保护的机制，我们将线粒体解偶联和假定AMP活化蛋白激酶（AMPK）的生物能后果视为HUCP2的下游效应子。在支持这一想法时，我们检测到磷酸化的AMPK。当果蝇S2R+细胞中诱导HUCP2表达时，它表明了其激活。与我们的遗传相互作用研究一致，揭示了HUCP2和线粒体融合分子之间的功能合作，我们当前的结果表明HUCP2神经保护作用需要线粒体融合。此外，自噬活性增加与脑DA神经元中的HUCP2表达有关。结果表明，在表达原发性DA神经元的HUCP2或AMPK中，对毒素诱导的线粒体碎裂的结果表明，对毒素诱导的神经元损失的AMPK受保护作用与自动噬菌体损失相关联（2）p（2）p的较小相关。综上所述，这些初步结果使我们假设AMPK的激活是HUCP2表达的结果促进了线粒体融合和自噬，从而增强了DA神经元的线粒体健康和生存。要检验我们的假设，我们将确定i）AMPK是否是HUCP2在确定DA神经元线粒体融合/裂变方面是否是DA神经元中的线粒体融合/裂变的下游效应子，II）ii）AMPK是否刺激了对毒素和III的DA神经元的自噬性和线粒体的跨性别型和iii da neurons in to toxin and III）是否易于构想。对毒素的神经元生存。