Molecular Mechanisms of Neuroprotection in Polyglutamine-Dependent Degeneration

多谷氨酰胺依赖性变性中神经保护的分子机制

• 批准号: 9234079
• 负责人: Sokol Todi
• 金额: $ 33.25万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234079
• 关键词: Animal Model; Ataxia; Biochemical; Biological; Biological Models; Cells; Cellular biology; Disease; Drosophila genus; Drosophila melanogaster; Etiology; Family; Genes; Goals; Health; Human; Huntington Disease; In Vitro; Laboratories; Lead; Length; MJD1 protein; Machado-Joseph Disease; Methods; Modeling; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organism; Pathogenicity; Pathology; Pathway interactions; Physiological; Postdoctoral Fellow; Process; Protein Region; Proteins; Retinal Degeneration; Symptoms; Testing; Therapeutic; Ubiquitination; Work; age related; combat; compound eye; fly; neuroprotection; novel; polyglutamine; protein degradation; protein protein interaction; public health relevance; screening

DESCRIPTION (provided by applicant): Spinocerebellar Ataxia Type 3 (SCA3, also known as Machado-Joseph Disease) belongs to the family of polyglutamine-dependent neurodegenerative disorders that also includes Huntington's Disease and several other SCAs. SCA3, which is the most common dominant ataxia in the world, is caused by large expansions in the polyglutamine tract of the protein ataxin-3. Current therapeutic approaches for the treatment of SCA3 are symptomatic and do not address the core etiology. Animal models of polyglutamine diseases have shown that reducing the levels of the causative protein leads to significant improvement in neuronal pathology and symptoms. This suggests that enhancing the degradation of the ataxin-3 protein provides a reasonable approach to treat SCA3. The long-term goal of my laboratory is to elucidate molecular mechanisms involved in neurodegeneration and neuroprotection. Starting during my postdoctoral work, I focused on pathways involved in protein degradation, and specifically on ataxin-3. In the course of trying to understand the cell biology of ataxin-3 as a point of entry for SCA3 therapy, we made the unexpected finding that the degradation of ataxin-3 is not regulated by ubiquitination in the common sense. Instead, pathogenic ataxin-3 is stabilized by its interaction with the proteasomal shuttle proteins Rad23 and VCP. Our novel finding provided a lead to destabilize pathogenic ataxin-3 for therapy. This strategy is made even more plausible by the ability of cells and organisms to tolerate very low levels of ataxin-3 - in other words, without a restrictive therapeutic window in terms of the cellular levels of ataxin-3. Here, we propose to expand on these exciting findings by determining how ataxin-3 is degraded, with special emphasis on Rad23 and VCP, and by subsequently testing the idea that disrupting these interactions suppresses ataxin-3-dependent degeneration in the genetically tractable model organism Drosophila melanogaster. We then plan to take advantage of this model system to discover novel genes that suppress ataxin-3-dependent degeneration.

描述（由申请人提供）：脊髓小脑性共济失调3型（SCA 3，也称为Machado-Joseph病）属于多聚谷氨酰胺依赖性神经退行性疾病家族，也包括亨廷顿病和几种其他SCA。SCA 3是世界上最常见的显性共济失调，是由蛋白共济失调蛋白-3的多聚谷氨酰胺束中的大量扩张引起的。目前用于治疗SCA 3的治疗方法是对症的，并且不解决核心病因。多聚谷氨酰胺疾病的动物模型已经表明，降低致病蛋白的水平导致神经元病理学和症状的显著改善。这表明增强共济失调蛋白-3蛋白的降解提供了治疗SCA 3的合理方法。我实验室的长期目标是阐明神经变性和神经保护的分子机制。从我的博士后工作开始，我专注于蛋白质降解的途径，特别是ataxin-3。在试图理解共济失调蛋白-3的细胞生物学作为SCA 3治疗的切入点的过程中，我们意外地发现共济失调蛋白-3的降解不受常识中的泛素化的调节。相反，致病性共济失调蛋白-3通过其与蛋白酶体穿梭蛋白Rad 23和VCP的相互作用而稳定。我们的新发现为治疗提供了使致病性共济失调蛋白-3不稳定的线索。细胞和生物体能够耐受非常低水平的共济失调蛋白-3，换句话说，在共济失调蛋白-3的细胞水平方面没有限制性的治疗窗口，这使得这种策略更加合理。在这里，我们建议扩大这些令人兴奋的发现，确定如何ataxin-3降解，特别强调Rad 23和VCP，并随后测试的想法，破坏这些相互作用抑制ataxin-3依赖变性的遗传听话的模式生物果蝇。然后，我们计划利用这个模型系统来发现抑制共济失调蛋白-3依赖性变性的新基因。