Molecular Mechanisms of Neuroprotection in Polyglutamine-Dependent Degeneration

描述(申请人提供)：脊髓-小脑型共济失调3型(SCA3，也称为马查多-约瑟夫病)属于多谷氨酰胺依赖型神经退行性疾病家族，还包括亨廷顿病和其他几个SCA。SCA3是世界上最常见的主导性共济失调，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的治疗方法是有症状的，没有解决核心病因。聚谷氨酰胺病的动物模型表明，降低致病蛋白水平会显著改善神经元的病理和症状。这表明促进ataxin-3蛋白的降解为治疗SCA3提供了一种合理的方法。我的实验室的长期目标是阐明神经退变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ataxin-3作为SCA3治疗切入点的细胞生物学的过程中，我们获得了意想不到的发现，即ataxin-3的降解不受常识中泛素化的调节。相反，致病的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。我们的新发现为破坏致病的ataxin-3的治疗提供了线索。由于细胞和生物体能够耐受极低水平的ataxin-3，换句话说，就细胞内ataxin-3的细胞水平而言，没有限制性的治疗窗口，这一策略变得更加合理。在这里，我们建议通过确定ataxin-3是如何降解的，特别是RAD23和VCP，并随后测试破坏这些相互作用可以抑制遗传易驯化的模式生物黑腹果蝇中ataxin-3依赖的退化的想法，来扩展这些令人兴奋的发现。然后，我们计划利用这个模型系统来发现抑制依赖于ataxin-3的退化的新基因。

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.