Rhes-SUMO circuitry in Huntington's Disease Pathogenesis

亨廷顿病发病机制中的 Rhes-SUMO 电路

• 批准号: 9006888
• 负责人: Srinivasa Subramaniam
• 金额: $ 42万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9006888
• 关键词: Affect; Animal Model; Autophagocytosis; Behavior; Behavioral; Binding; Biochemical; Biochemistry; Biological Assay; Biology; Body Weight; Brain; Cell Culture Techniques; Cells; Cellular biology; Cessation of life; Cognitive; Corpus striatum structure; Data; Defect; Deterioration; Development; Disease; Disease model; Drug Targeting; Dyskinetic syndrome; Etiology; Functional disorder; Gene Expression; Genes; Genetic; Glutamine; Goals; Guanosine Triphosphate Phosphohydrolases; Hereditary Disease; Homologous Gene; Human; Huntington Disease; Huntington gene; In Vitro; Knockout Mice; Knowledge; Kyphosis deformity of spine; Limb structure; Mammals; Mediating; Mission; Mitochondria; Molecular; Morphology; Mus; Neurodegenerative Disorders; Neurons; Outcome; Pain; Pathogenesis; Pathway interactions; Peripheral; Personality; Pharmaceutical Preparations; Phenotype; Physiological; Play; Prevention; Preventive; Process; Proteins; Proteomics; Public Health; Publishing; Research; Role; Signal Transduction; Specificity; Staining method; Stains; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Transgenic Organisms; Work; base; cognitive function; disability; disease phenotype; in vivo; innovation; insight; interdisciplinary approach; mitochondrial dysfunction; motor control; mouse model; mutant; neuron loss; novel; novel therapeutics; open field behavior; paralogous gene; polyglutamine; prevent; public health relevance; reconstitution; symptom treatment; tool; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine repeat in the protein huntingtin (mHtt), and is manifested by choreatic dyskinesias, personality changes, abnormal behaviors and cognitive deterioration. With the exception of symptomatic treatments there are no disease-modifying therapies for HD. Although mHtt is expressed ubiquitously in brain and peripheral tissue, it predominantly causes neuronal loss and damage in striatal tissue, a process that is poorly understood. Therefore, studies that define the mechanisms that contribute to the striatal degeneration are needed to develop new drugs that prevent and/or delay the onset of HD. Our long-term goal is to understand the role of striatal-specific proteins in HD pathogenesis for preventive and therapeutic purposes. The objective here, which is next step in pursuit of that goal, is to dissect the mechanisms of Rhes GTPase, that contains SUMO E3 ligase activity, in HD pathogenesis, and to identify its physiological SUMO substrates. Our central hypothesis is that Rhes-SUMO1-mHtt-mTORC1 circuitry elicits mitochondrial damage and HD pathogenesis. This hypothesis is formulated on the basis of our previous studies, new data and preliminary results. Our Aims are: 1: Dissect the role of Rhes-SUMO-mHtt-mTORC1 circuitry in mitochondrial dysfunction. Multiple studies support the role of Rhes in HD, but the mechanisms are unknown. Here we will dissect the mechanisms, using striatal cells, focusing on the Rhes-SUMO1 in mTORC1 activity and mitochondrial dysfunction; and 2: Challenge the deletion of SUMO1 in the amelioration of HD pathogenesis in mice. Despite known roles for SUMO1 in mHtt-induced cellular toxicity, its role in the pathogenesis of HD in mammal remains unknown. We will cross SUMO1-/- mice with N171HD mouse to elucidate behavioral and pathological outcomes; and 3: Identify SUMOylation substrates for Rhes. Besides SUMOylating mHtt, Rhes physiologically SUMOylates several striatal proteins, but their identity remains unknown. Using cell culture, in vitro SUMOylation assay, and proteomic approaches we will identify potential SUMO substrates for Rhes. Overall, the project is innovative because it employs an interdisciplinary approach, utilizing tools from mouse genetics, cell biology, biochemistry, and behavior to dissect the pathway leading to striatal-specific cell loss. The results of this project will be significant, as it will advance our understanding of why striatal tissue is preferentially ost in an mHtt- dependent fashion and provide proof-of-principle for the development of drugs targeting Rhes signaling in HD.

 描述（由适用提供）：亨廷顿疾病（HD）是一种常染色体显性神经退行性疾病，是由蛋白质亨廷顿蛋白（MHTT）中多谷氨酰胺重复膨胀引起的，并且由脉络化性运动障碍表现出来，由人格变化，人格变化，异常行为和认知能力确定。除症状治疗外，没有针对HD的疾病改良疗法。尽管MHTT在脑和周围组织中普遍存在，但它主要导致纹状体组织的神经元丧失和损害，这一过程知之甚少。因此，需要进行定义有助于纹状体变性的机制的研究，以开发预防和/或延迟HD发作的新药物。我们的长期目标是了解纹状体特异性蛋白在HD发病机理中的作用，以进行预防和治疗目的。这是追求该目标的下一步的目的是剖析rhes gtpase的机制，该机理包含SUMO E3连接酶活性，HD发病机理，并识别其物理EMO底物。我们的中心假设是Rhes-Sumo1-MHTT-MTORC1电路会引起线粒体损伤和HD发病机理。该假设是根据我们先前的研究，新数据和初步结果提出的。我们的目标是：1：剖析线粒体功能障碍中Rhes-Sumo-MHTT-MTORC1电路的作用。多项研究支持Rhes在HD中的作用，但是这些机制尚不清楚。在这里，我们将使用纹状体细胞解剖机制，重点是MTORC1活性和线粒体功能障碍中的Rhes-Sumo1。和2：挑战SUMO1在小鼠中HD发病机理改善中的缺失。尽管已知SUMO1在MHTT诱导的细胞毒性中的作用已知，但其在HD发病机理中的作用仍然未知。我们将用N171HD小鼠穿越SUMO1 - / - 小鼠，以阐明行为和病理结果。和3：确定恒星的sumoylation底物。除了sumoylating MHTT外，Rhes还可以物理地覆盖几种纹状体蛋白，但它们的身份仍然未知。使用细胞培养，体外sumoylation分析和蛋白质组学方法，我们将确定恒星的潜在相扑底物。总体而言，该项目具有创新性，因为它采用了跨学科方法，使用小鼠遗传学，细胞生物学，生物化学和行为的工具来剖析导致纹状体特异性细胞损失的途径。这个项目的结果 将是重要的，因为它将促进我们对为什么纹状体组织以MHTT依赖性方式更有可能OST的理解，并为靶向HD中Rhes信号的药物的开发提供原则证明。