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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：
8744411
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/8744411
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 Data Development Disease Disease model Dynamin Exons Family Gene Mutation Genes Glutamine Goals Guanosine Triphosphate Phosphohydrolases Human Huntington Disease Image 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 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 public health relevance research study tool

项目摘要

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.

亨廷顿氏病（HD）是一种致命的常染色体显性遗传神经退行性疾病，亨廷顿基因外显子1内的谷氨酰胺编码CAG扩增。虽然基因突变虽然已经确定了与该病相关的基因，但尚不清楚HD的分子和细胞基础并且这种疾病的成功治疗仍然难以捉摸。基础研究和临床研究表明，线粒体功能障碍在HD的发病机制中起重要作用。线粒体是以高度动态的管状网络，通过相反的融合和裂变过程不断重塑。动力蛋白相关蛋白1（Dynamin-related protein 1，Drp 1）是一个大的GT3，是控制线粒体分裂的关键蛋白。最近研究强调了Drp 1介导的过度线粒体分裂在神经元死亡中的因果作用。 HD细胞培养模型。然而，Drp 1过度活化如何介导线粒体损伤， HD中的神经变性以及药物抑制Drp 1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。我们最近的研究表明， Drp 1在HD细胞培养物和HD中的体内都易位到线粒体并过度活化。 R6/2转基因小鼠脑。重要的是，最近使用一种新型的选择性Drp 1肽抑制剂P110，我们发现，抑制Drp 1依赖的线粒体损伤， HD细胞培养物中的线粒体功能障碍和神经元细胞死亡，并减少行为缺陷和损失 HDR 6/2转基因小鼠纹状体神经元的变化。此外，用P110处理校正了线粒体形态和减少的神经突损失和细胞死亡的GABA能纹状体神经元衍生自HD患者- 诱导多能干细胞（HD-iPS细胞）。此外，使用无偏蛋白质组学分析，我们最近分析了 HD患者-iPS细胞神经元培养物中Drp 1的相互作用组。我们的初步研究鉴定了两种机制不同的候选蛋白（ATADA 3，线粒体AAA-ATPase的成员家族和MAPK 1，一种丝氨酸/苏氨酸激酶），其参与Drp 1介导的神经元损伤。这些一系列证据表明Drp 1过度激活是HD神经变性的主要原因。因此，在本发明中，我们假设抑制Drp 1介导的线粒体损伤是一种新的方法，在体外和体内HD模型中的神经病理学。利用生物化学，成像，生物能量，蛋白质组学和从动物到患者神经元的药理学方法，我们在此应用中的目标是解开 Drp 1介导的线粒体功能障碍在神经退行性变中的复杂性，治疗细节这项研究将产生新的信息Drp 1介导的作用，线粒体分裂在HD的发病机制，并提供了一个有用的模型系统，在其中研究纹状体神经元的线粒体病理学。我们还将开发药物工具来抑制HD 发病机制作为第一步的发展新的治疗HD。