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Dynamin-related protein 1, neurodegeneration and Huntington's disease

动力相关蛋白 1、神经变性和亨廷顿病

基本信息

批准号：
8848902
负责人：
XIN QI
金额：
$ 34.67万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8848902
关键词：
ATP phosphohydrolase Animal Model Animals Basic Science Behavior Behavioral Biochemical Biological Models Brain Cell Culture Techniques Cell Death Cells Cessation of life Chronic Clinical Research Code Complex Corpus striatum structure DNA Sequence Alteration Data Development Disease Disease model Dynamin Exons Family Genes Glutamine Goals Guanosine Triphosphate Phosphohydrolases Health Human Huntington Disease Impairment In Vitro Length MAPK1 gene Mediating Mitochondria Modeling Molecular Morphology Mus Nerve Degeneration Neurites Neurodegenerative Disorders Neurologic Neurons Pathogenesis Pathology Patients Peptides Play Process Protein-Serine-Threonine Kinases Proteins Proteomics Reagent Role Signal Transduction Symptoms Therapeutic Transgenic Mice Treatment Efficacy Tubular formation Work base bioimaging design effective therapy human Huntingtin protein in vivo induced pluripotent stem cell inhibitor/antagonist member mitochondrial dysfunction motor deficit mouse model mutant neuron loss neuropathology neurotoxicity novel novel strategies novel therapeutic intervention novel therapeutics protective effect protein protein interaction research study tool

项目摘要

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a fatal, autosomal dominant, neurodegenerative disorder caused by a glutamine-coding CAG expansion within exon 1 of the huntingtin gene. Although the genetic mutation associated with the disease has been identified, the molecular and cellular basis of HD is not yet understood and successful treatment for this disease remains elusive. Basic research and clinical studies indicate that mitochondrial dysfunction plays an important role in the pathogenesis of HD. Mitochondria are organized in a highly dynamic tubular network that is continuously reshaped by opposing processes of fusion and fission. Dynamin-related protein 1 (Drp1) is a large GTPase and a key protein governing mitochondrial fission. Recent studies have highlighted the causal role of Drp1-mediated excessive mitochondrial fission in neuronal death in HD cell culture models. However, how Drp1 hyperactivation mediates mitochondrial damage and neurodegeneration in HD and whether pharmacological inhibition of Drp1 activation is sufficient to reduce mutant Htt (mtHtt)-induced neurotoxicity and neurodegeneration are not known. Our recent work showed that Drp1 is translocated to the mitochondria and hyper-activated in both HD cell cultures and in vivo in the HD R6/2 transgenic mouse brain. Importantly, using a novel and selective peptide inhibitor of Drp1, P110, recently developed in our group, we found that inhibition of Drp1-dependent mitochondrial impairment corrected mitochondrial dysfunction and neuronal cell death in HD cell cultures, and reduced behavioral deficits and loss of striatal neurons in HD R6/2 transgenic mice. Moreover, treatment with P110 corrected mitochondrial morphology and reduced neurite loss and cell death in GABAergic striatal neurons derived from HD patient- induced pluripotent stem cells (HD-iPS cells). Further, using unbiased proteomic analysis, we recently profiled the interactome of Drp1 in neuronal cultures derived from HD patient-iPS cells. Our preliminary studies identified two mechanistically distinct candidate proteins (ATADA3, a member of mitochondrial AAA-ATPase family, and MAPK1, a serine/threonine kinase) that are involved in Drp1-mediated neuronal damage. These lines of evidence indicate that Drp1 hyperactivation is a predominant cause of neurodegeneration in HD. Thus, we hypothesize that inhibition of Drp1-mediated mitochondrial damage is a novel approach for reducing neuropathology in HD models in vitro and in vivo. Using biochemical, imaging, bio-energetic, proteomic and pharmacological approaches ranging from animals to patient neurons, our goal in this application is to unravel the complexity of Drp1-mediated mitochondrial dysfunction in neurodegeneration in both mechanistic and therapeutic detail. The proposed study will produce novel information on the role of Drp1-mediated mitochondrial fission in the pathogenesis of HD and provide a useful model system in which to study mitochondrial pathology in striatal neurons. We will also generate pharmacological tools to inhibit HD pathogenesis as a first step towards the development of novel therapeutics for HD.

描述（由申请人提供）：亨廷顿病 (HD) 是一种致命的常染色体显性神经退行性疾病，由亨廷顿基因外显子 1 内编码谷氨酰胺的 CAG 扩展引起。尽管与该疾病相关的基因突变已被确定，但 HD 的分子和细胞基础尚不清楚，并且该疾病的成功治疗仍然难以实现。基础研究和临床研究表明线粒体功能障碍在HD的发病机制中发挥着重要作用。线粒体被组织成一个高度动态的管状网络，该网络通过相反的融合和裂变过程不断重塑。动力相关蛋白 1 (Drp1) 是一种大型 GTP 酶，也是控制线粒体裂变的关键蛋白。最近的研究强调了 Drp1 介导的线粒体过度分裂在 HD 细胞培养模型中神经元死亡中的因果作用。然而，Drp1 过度激活如何介导 HD 中的线粒体损伤和神经变性，以及药物抑制 Drp1 激活是否足以减少突变型 Htt (mtHtt) 诱导的神经毒性和神经变性尚不清楚。我们最近的工作表明，Drp1 在 HD 细胞培养物和体内 HD R6/2 转基因小鼠大脑中易位至线粒体并高度激活。重要的是，使用我们小组最近开发的新型选择性 Drp1 肽抑制剂 P110，我们发现抑制 Drp1 依赖性线粒体损伤可纠正 HD 细胞培养物中的线粒体功能障碍和神经元细胞死亡，并减少 HD R6/2 转基因小鼠的行为缺陷和纹状体神经元损失。此外，P110治疗纠正了HD患者诱导多能干细胞（HD-iPS细胞）衍生的GABA能纹状体神经元的线粒体形态并减少了神经突丢失和细胞死亡。此外，利用无偏见的蛋白质组学分析，我们最近分析了 HD 患者 iPS 细胞的神经元培养物中 Drp1 的相互作用组。我们的初步研究确定了两种机制不同的候选蛋白（ATADA3，线粒体 AAA-ATP 酶家族的成员，和 MAPK1，丝氨酸/苏氨酸激酶），它们参与 Drp1 介导的神经元损伤。这些证据表明 Drp1 过度激活是 HD 神经变性的主要原因。因此，我们假设抑制 Drp1 介导的线粒体损伤是减少体外和体内 HD 模型神经病理学的一种新方法。使用从动物到患者神经元的生物化学、成像、生物能量、蛋白质组学和药理学方法，我们在该应用中的目标是从机制和治疗细节上揭示神经变性中 Drp1 介导的线粒体功能障碍的复杂性。拟议的研究将产生关于 Drp1 介导的线粒体裂变在 HD 发病机制中的作用的新信息，并提供一个有用的模型系统来研究纹状体神经元的线粒体病理学。我们还将开发抑制 HD 发病机制的药理学工具，作为开发 HD 新型疗法的第一步。