Investigation of the role of ATXN1 in oligodendroglia and neurodegenerative diseases

脊髓小脑共济失调1型（SCA 1）是一种常染色体显性遗传的进行性神经退行性疾病， 导致严重的运动缺陷和小脑神经元退化。它是由CAG重复扩增引起的， Ataxin-1（ATXN 1）基因。虽然ATXN 1在整个大脑中相当普遍地表达，但特定的大脑 已经显示出区域和细胞类型选择性地易受变性，包括小脑 浦肯野细胞神经元。为了更好地了解这种疾病的病理生理学， 已经被开发和广泛使用。然而，这些小鼠模型中的大多数已经被表征为 在特定的遗传背景下。例如，浦肯野细胞特异性转基因SCA 1模型已经被证实是有效的。 在纯FVB/NJ背景上开发和维持，包括表达人FVB/NJ的B 05模型， 致病ATXN 1等位基因，并概括了行为缺陷和病理表型观察到的 人SCA 1患者。有趣的是，当我们回交并保持这一原始B 05小鼠品系到一个 纯C57 BL/6 J遗传背景，SCA 1相关的行为运动缺陷不再观察到，然而， 浦肯野细胞变性表型仍然存在。这些初步研究结果表明， 背景在有效建模神经退行性疾病如SCA 1中起着至关重要的作用， 因此，应进一步分析小鼠遗传背景与疾病症状的相互作用， 在未来的实验中仔细控制。在这份补助金提案中，我们将确定 不同的小鼠遗传背景对SCA 1疾病表型的影响，并阐明了SCA 1疾病表型的分子机制。 ATXN 1突变体调节运动行为缺陷和浦肯野细胞变性的机制。在 目的1，我们将充分表征两种遗传背景之间的SCA 1小鼠表型差异。 在目标2中，我们将确定SCA 1小鼠小脑中受到差异影响的分子途径 两种不同的遗传背景。我们预计，这项研究将提供基本的见解， 研究小鼠遗传背景对神经退行性疾病发病机制的影响，并揭示 SCA 1病理学调节的新机制。如果成功，这些研究将强调 检查神经退行性疾病中多种遗传背景的重要性并揭示新的潜力 在与ATXN 1突变相关的疾病中进行治疗干预的切入点，包括SCA 1， 额颞叶痴呆症和阿尔茨海默病

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant, progressive neurodegenerative disease that causes severe motor deficits and cerebellar neuron degeneration. It is caused by a CAG-repeat expansion in the gene Ataxin-1 (ATXN1). Although ATXN1 is fairly ubiquitously expressed throughout the brain, specific brain regions and cell types have been shown to be selectively vulnerable to degeneration, including cerebellar Purkinje cell neurons. In order to better understand the pathophysiology of this disease, several mouse models have been developed and extensively utilized. However, most of these mouse models have been characterized on a particular genetic background. For example, the Purkinje cell-specific transgenic SCA1 models have been developed and maintained on a pure FVB/NJ background, including the B05 model, which express the human disease-causing ATXN1 allele and recapitulate the behavioral deficits and pathological phenotypes observed in human SCA1 patients. Interestingly, when we backcrossed and maintained this original B05 mouse line onto a pure C57BL/6J genetic background, the SCA1-related behavioral motor deficit was no longer observed, however the Purkinje cell degeneration phenotypes remained. These preliminary findings suggest that mouse genetic background plays a crucial role in effectively modeling neurodegenerative diseases, such as SCA1, and therefore, the interaction of mouse genetic background and disease symptoms should be further analyzed and carefully controlled for in future experiments. In this supplement grant proposal, we will determine the precise impact of different mouse genetic backgrounds towards SCA1 disease phenotypes, and elucidate the molecular mechanisms through which mutant ATXN1 regulates motor behavior deficits and Purkinje cell degeneration. In Aim 1, we will fully characterize the SCA1 mouse phenotypic differences between the two genetic backgrounds. In Aim 2, we will determine the molecular pathways differentially affected in the SCA1 mouse cerebellum between two different genetic backgrounds. We anticipate that this research will provide fundamental insights into the impact of mouse genetic backgrounds towards neurodegenerative disease pathogenesis, and uncover novel mechanisms through which SCA1 pathology is regulated. If successful, these studies will underscore the importance of examining multiple genetic backgrounds in neurodegenerative diseases and reveal novel potential entry points for therapeutic intervention in disorders in which ATXN1 mutations are associated, including SCA1, frontotemporal dementia, and Alzheimer’s disease.