Investigation of the role of ATXN1 in oligodendroglia and neurodegenerative diseases

脊髓小脑性共济失调1型(SCA1)是一种常染色体显性遗传性进行性神经退行性疾病， 会导致严重的运动障碍和小脑神经元变性。它是由CAG-重复扩张引起的 基因Aaxin-1(ATXN1)虽然ATXN1在整个大脑中都有相当普遍的表达，但特定的大脑 研究表明，区域和细胞类型选择性地容易变性，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机制，几种小鼠模型 已得到开发和广泛利用。然而，这些老鼠模型中的大多数都已被描述为 在特定的遗传背景下。例如，Purkinje细胞特异性转基因SCA1模型已经被 在纯FVB/NJ背景下开发和维护，包括B05模型，表示人类 致病的ATXN1等位基因，并概述了观察到的行为缺陷和病理表型 人类SCA1患者。有趣的是，当我们将这个原始的B05小鼠品系回交并保持到 纯C57BL/6J遗传背景，然而，SCA1相关的行为运动缺陷不再被观察到 浦肯野细胞退行性变表型仍然存在。这些初步发现表明，小鼠的基因 背景在有效模拟神经退行性疾病，如SCA1，和 因此，应进一步分析小鼠遗传背景与疾病症状的交互作用。 在未来的实验中仔细控制。在这项补充补助金建议中，我们将确定准确的 不同小鼠遗传背景对SCA1疾病表型的影响及其分子机制 突变型ATXN1调节运动行为缺陷和浦肯野细胞退化的机制。在……里面 目的1，我们将充分表征SCA1小鼠在两种遗传背景下的表型差异。 在目标2中，我们将确定在sca1小鼠小脑中受到不同影响的分子通路。 在两个不同的遗传背景之间。我们预计，这项研究将提供基本的见解 进入小鼠遗传背景对神经退行性疾病发病机制的影响，并揭示 调控SCA1病理的新机制。如果成功，这些研究将强调 检测多种遗传背景在神经退行性疾病中的重要性并揭示新的潜力 ATXN1突变相关疾病治疗干预的切入点，包括SCA1， 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.