Molecular Mechanisms of Neuroprotection in Polyglutamine-Dependent Degeneration

描述（由申请人提供）：脊髓小脑性共济失调3型（SCA3，也称为Machado-Joseph病）属于多谷氨酰胺依赖性神经退行性疾病家族，该家族还包括亨廷顿病和其他几种SCAs。SCA3是世界上最常见的显性共济失调，是由蛋白ataxin-3的聚谷氨酰胺束大量扩张引起的。目前治疗SCA3的治疗方法是对症治疗，没有解决核心病因。多谷氨酰胺疾病的动物模型表明，降低致病蛋白的水平可显著改善神经元病理和症状。这表明增强ataxin-3蛋白的降解为治疗SCA3提供了一种合理的途径。我的实验室的长期目标是阐明参与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。在试图了解ataxin-3作为SCA3治疗切入点的细胞生物学过程中，我们意外地发现，在常识中，ataxin-3的降解不受泛素化的调节。相反，致病性ataxin-3通过与蛋白酶体穿梭蛋白Rad23和VCP的相互作用而稳定下来。我们的新发现为不稳定致病性ataxin-3的治疗提供了线索。细胞和生物体耐受极低水平的ataxin-3的能力使这一策略更加合理——换句话说，就细胞水平而言，没有限制ataxin-3的治疗窗口。在这里，我们建议通过确定ataxin-3如何降解来扩展这些令人兴奋的发现，特别强调Rad23和VCP，并随后测试破坏这些相互作用抑制遗传易感模式生物果蝇中ataxin-3依赖性退化的想法。然后我们计划利用这个模型系统来发现抑制ataxin-3依赖性变性的新基因。

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.