Mitochondrial Fission in Huntington's Disease

亨廷顿病中的线粒体裂变

基本信息

批准号：
7389367
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
项目类别：
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/7389367
关键词：
Address Algorithms Apoptosis Apoptotic Autopsy Autosomal Dominant Optic Atrophy Biochemistry and Pharmacology Cancer Activity Bioenergetics Blindness Buffers Cell Death Cells Charcot-Marie-Tooth Disease Child Chronic Complex Condition 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 Localized 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 Play Potential Energy Process Production Proteins Publications Reactive Oxygen Species Recruitment Activity Respiration Role Sensory Site Spottings Structure Symptoms Synaptic Transmission Taxes Techniques Testing Time Transgenic Mice base brain tissue cancer cell caregiving cost cytochrome c 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

项目摘要

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）：亨廷顿氏病（HD）是一种遗传神经退行性疾病，是由亨廷顿蛋白（HTT）蛋白质异常的聚谷氨酰胺（PolyQ）膨胀引起的，导致进行性痴呆，运动缺陷，运动缺陷和精神上的异常。目前，高清保持无法治愈。在高清纹状体和皮质神经元中，通过未知机制有选择地死亡。迫切需要进行科学突破，以揭示突变体HTT如何导致神经元灭亡。出现了新的证据，表明线粒体功能障碍在HD基础发病机理中起着核心作用。但是，确切地说，线粒体在高清中受伤仍然不清楚。线粒体是能够迁移，分裂（进行裂变）和融合的动态细胞器。线粒体裂变和融合通过与竞争活动的Dynamin相关GTPase编排。在正常条件下，线粒体形成神经元中的电缆状丝，可有效地传递能量，代谢产物的混合，Ca2+缓冲和mtDNA突变的沉默。在这里，我们将测试新的假设是否持续的线粒体裂变代表与HD发病机理有关的线粒体功能障碍的机械基础。我们将解决以下问题：（1）突变HTT是否触发连续的线粒体裂变，进而导致线粒体的超微结构损害，能量缺陷，线粒体呼吸受损，ROS产生，ROS的产生，异常CA2+ CA2+稳态和MTDNA丧失？（2）突变体HTT是否募集并激活线粒体裂变机械？（3）线粒体裂变是否在突变体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，我们将隔离原发性纹状体或皮质神经元。此外，我们将采用突变的HTT转基因小鼠和验尸HD脑组织。我们将使用跨学科和先进技术（包括3D时间解体成像，EM断层扫描，分子遗传学，药理学，生物化学和生物能学）分析它们。我们还将开发新的算法，以通过3D延时成像来量化线粒体裂变和MTHTT骨料形成。这项研究将提高我们对突变HTT如何触发神经元灭亡的基本理解。此处获得的结果可能为HD和其他PolyQ疾病的代谢和线粒体缺陷提供了新的机械基础。最重要的是，这项研究可能给有效的治疗方法带来新的希望，以征服HD的进行性神经元丧失，因此患者可以过上改善的生活。