Rhes-SUMO circuitry in Huntington's Disease Pathogenesis

亨廷顿病发病机制中的 Rhes-SUMO 电路

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：亨廷顿病（HD）是一种常染色体显性神经退行性疾病，由亨廷顿蛋白（mHtt）中的聚谷氨酰胺重复序列扩增引起，表现为舞蹈性运动障碍、性格改变、行为异常和认知能力下降。尽管 mHtt 在大脑和外周组织中普遍表达，但它主要导致 HD。因此，我们的长期目标是开发预防和/或延缓 HD 发作的新药物。旨在了解纹状体特异性蛋白在 HD 发病机制中的作用，以达到预防和治疗的目的。下一步的目标是剖析包含 SUMO E3 连接酶活性的 Rhes GTPase 的机制，我们的中心假设是 Rhes-SUMO1-mHtt-mTORC1 电路引起线粒体损伤和 HD 发病机制，该假设是根据我们之前的研究、新数据和初步结果提出的。我们的目标是： 1：剖析 Rhes-SUMO-mHtt-mTORC1 电路在线粒体功能障碍中的作用多项研究支持 Rhes 在 HD 中的作用，但其机制是。在这里，我们将使用纹状体细胞剖析其机制，重点关注 mTORC1 活性和线粒体功能障碍中的 Rhes-SUMO1；以及 2：尽管已知 SUMO1 在 mHtt 中的作用，但挑战 SUMO1 的缺失可改善 HD 发病机制。诱导的细胞毒性，其在哺乳动物 HD 发病机制中的作用仍不清楚。我们将 SUMO1-/- 小鼠与 N171HD 小鼠杂交以阐明行为和病理。结果；3：鉴定Rhes 的SUMO 化底物。除了SUMO 化mHtt 之外，Rhes 还能对几种纹状体蛋白进行SUMO 化，但它们的身份仍然未知。我们将利用细胞培养、体外SUMO 化分析和蛋白质组学方法鉴定Rhes 的潜在SUMO 底物。该项目具有创新性，因为它采用了跨学科方法，利用小鼠遗传学、细胞生物学、生物化学和行为学的工具来剖析导致该项目的结果是纹状体特异性细胞损失。将会很重要，因为它将增进我们对为什么纹状体组织优先以 mHtt 依赖性方式发生的理解，并为 HD 中 Rhes 信号传导靶向药物的开发提供原理验证。