Mitochondrial Fission in Huntington's Disease

亨廷顿病中的线粒体裂变

• 批准号: 7558280
• 负责人: Ella R Bossy-Wetzel
• 金额: $ 30.95万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7558280
• 关键词: Address; Afferent Neurons; Algorithms; Apoptosis; Apoptotic; Autopsy; Autosomal Dominant Optic Atrophy; Biochemistry; Bioenergetics; Blindness; Buffers; Cell Death; Cells; Charcot-Marie-Tooth Disease; Child; Chronic; Complex; Corpus striatum structure; Defect; Dementia; Disease; Dominant-Negative Mutation; Drops; Drug Delivery Systems; Dynamin; Emotional; Equilibrium; Event; Exhibits; Filament; Funding; Future; Glutamates; Glutamine; Goals; Guanosine Triphosphate Phosphohydrolases; Homeostasis; Human; Huntington Disease; Image; Inherited; Ion Pumps; Lead; Life; Mediating; Membrane Potentials; Memory; Metabolic; Mitochondria; Mitochondrial DNA; Molecular; Molecular Genetics; Motor; Motor Skills; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Nitric Oxide; Optic Nerve; Organelles; Outer Mitochondrial Membrane; Pathogenesis; Pathway interactions; Patients; Pharmacology; Play; Potential Energy; Process; Production; Proteins; Publications; Reactive Oxygen Species; Recruitment Activity; Respiration; Role; Site; Spottings; Structure; Symptoms; Synaptic Transmission; Taxes; Techniques; Testing; Time; Transgenic Mice; base; brain tissue; cancer cell; caregiving; cost; cytochrome c; effective therapy; fighting; fusion gene; human Huntingtin protein; improved; injured; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial membrane; mutant; neuron loss; neurotoxic; neurotoxicity; novel; polyglutamine; prevent; respiratory; respiratory complex II; tomography; transmission process

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a hereditary neurodegenerative disorder and is caused by an abnormal polyglutamine (polyQ) expansion in the huntingtin (htt) protein, leading to progressive dementia, motor defects and psychiatric abnormalities. Presently, HD remains without cure. In HD striatal and cortical neurons die selectively by an unknown mechanism. Scientific breakthroughs are desperately needed to unravel how mutant htt causes neuronal demise. New evidence emerged indicating that mitochondrial dysfunction plays a central role in the pathogenesis underlying HD. But, exactly how mitochondria become injured in HD remains unclear. Mitochondria are dynamic organelles able to migrate, divide (undergo fission) and to fuse. Mitochondrial fission and fusion is choreographed by dynamin-related GTPases with competing activities. At normal conditions mitochondria form cable-like filaments in neurons, allowing efficient energy transmission, mixing of metabolites, Ca2+ buffering, and silencing of mtDNA mutations. Here, we will test the novel hypothesis whether persistent mitochondrial fission represents a mechanistic basis for the mitochondrial dysfunction implicated in HD pathogenesis. We will address the following questions: (1) Does mutant htt trigger continuous mitochondrial fission, which in turn results in ultrastructural damage of mitochondria, energy deficits, impaired mitochondrial respiration, ROS production, abnormal Ca2+ homeostasis, and mtDNA loss? (2) Does mutant htt recruit and activate the mitochondrial fission machinery? (3) Does mitochondrial fission play a causal role in mutant htt-induced neurodegeneration and cell death? To answer these questions we will isolate primary striatal or cortical neurons. Additionally, we will employ mutant htt transgenic mice and postmortem HD brain tissue. We will analyze them using interdisciplinary and advanced techniques including 3D timelapse imaging, EM tomography, molecular genetics, pharmacology, biochemistry, and bioenergetics. We will also develop new algorithms to quantify mitochondrial fission and mthtt aggregate formation by 3D time-lapse imaging. This study will improve our basic understanding of how mutant htt triggers neuronal demise. Results obtained here may offer a new mechanistic basis for the metabolic and mitochondrial defects underlying HD and perhaps other polyQ disease. Most importantly, this study may bring new hopes for effective treatments to conquer progressive neuron loss in HD, so patients can lead improved lives.

描述（由申请人提供）：亨廷顿病（HD）是一种遗传性神经退行性疾病，由亨廷顿蛋白（htt）中异常的聚谷氨酰胺（polyQ）扩增引起，导致进行性痴呆、运动缺陷和精神异常。目前，HD 仍无法治愈。在 HD 中，纹状体和皮质神经元通过未知机制选择性死亡。迫切需要科学突破来解开突变 htt 如何导致神经元死亡。新的证据表明线粒体功能障碍在 HD 的发病机制中起着核心作用。但是，线粒体在 HD 中究竟是如何受损的仍不清楚。线粒体是动态细胞器，能够迁移、分裂（裂变）和融合。线粒体裂变和融合是由具有竞争活性的动力相关 GTP 酶精心设计的。在正常情况下，线粒体在神经元中形成电缆状细丝，从而实现有效的能量传输、代谢物的混合、Ca2+缓冲和线粒体DNA突变的沉默。在这里，我们将检验这一新假设，即持续线粒体裂变是否代表 HD 发病机制中线粒体功能障碍的机制基础。我们将解决以下问题：（1）突变体htt是否会引发持续的线粒体裂变，从而导致线粒体超微结构损伤、能量不足、线粒体呼吸受损、ROS产生、Ca2+稳态异常和mtDNA丢失？ (2) 突变体 htt 是否会募集并激活线粒体裂变机制？ (3) 线粒体裂变是否在突变 htt 诱导的神经变性和细胞死亡中起因果作用？为了回答这些问题，我们将分离初级纹状体或皮质神经元。此外，我们将使用突变 htt 转基因小鼠和死后 HD 脑组织。我们将使用跨学科和先进的技术来分析它们，包括 3D 延时成像、EM 断层扫描、分子遗传学、药理学、生物化学和生物能量学。我们还将开发新的算法，通过 3D 延时成像来量化线粒体裂变和 mthtt 聚集体的形成。这项研究将提高我们对突变 htt 如何触发神经元死亡的基本理解。这里获得的结果可能为 HD 和其他 PolyQ 疾病的代谢和线粒体缺陷提供新的机制基础。最重要的是，这项研究可能为克服 HD 中进行性神经元丢失的有效治疗带来新的希望，从而改善患者的生活。