Investigation of the role of ATXN1 in oligodendroglia and neurodegenerative diseases

ATXN1 在少突胶质细胞和神经退行性疾病中的作用研究

• 批准号: 10632309
• 负责人: Janghoo Lim
• 金额: $ 2.51万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10632309
• 关键词: Affect; Alleles; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Applications Grants; Backcrossings; Behavioral; Brain; Brain region; CAG repeat; Cerebellum; Disease; Disease Progression; Frontotemporal Dementia; Functional disorder; Future; Genes; Genetic; Human; Investigation; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oligodendroglia; Onset of illness; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Play; Purkinje Cells; Research; Role; Symptoms; Therapeutic; Therapeutic Intervention; Transgenic Organisms; Type 1 Spinocerebellar Ataxia; ataxin-1; brain cell; cell type; disease phenotype; experimental study; human disease; insight; motor behavior; motor deficit; mouse genetics; mouse model; mutant; novel

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.

脊髓小脑共济失调 1 型 (SCA1) 是一种常染色体显性遗传、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变性，它是由 CAG 重复扩张引起的。 基因 Ataxin-1 (ATXN1) 虽然 ATXN1 在整个大脑中相当普遍地表达，但特定的大脑。 已证明某些区域和细胞类型选择性地容易发生变性，包括小脑 为了更好地了解这种疾病的病理生理学，研究了几种小鼠模型。 然而，这些小鼠模型中的大多数已经被表征。 例如，浦肯野细胞特异性转基因 SCA1 模型已被开发出来。 在纯FVB/NJ背景上开发和维护，包括B05模型，表达了人类 致病 ATXN1 等位基因并概括观察到的行为缺陷和病理表型 当我们将这个原始的 B05 小鼠品系回交并维持在人类 SCA1 患者身上时，结果令人满意。 纯 C57BL/6J 遗传背景，但不再观察到 SCA1 相关的行为运动缺陷 这些初步发现表明小鼠的浦肯野细胞变性表型仍然存在。 背景在有效建模神经退行性疾病（例如 SCA1）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，在这个补充拨款提案中，我们将确定精确的。 不同小鼠遗传背景对 SCA1 疾病表型的影响，并阐明分子机制 突变体 ATXN1 调节运动行为缺陷和浦肯野细胞变性的机制。 目标 1，我们将充分表征两种遗传背景之间的 SCA1 小鼠表型差异。 在目标 2 中，我们将确定 SCA1 小鼠小脑中受到差异影响的分子途径 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 如果成功，这些研究将强调 SCA1 病理学调节的新机制。 检查神经退行性疾病中多种遗传背景并揭示新潜力的重要性 治疗干预与 ATXN1 突变相关的疾病的切入点，包括 SCA1、 额颞叶痴呆和阿尔茨海默病。