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

基本信息

批准号：
10390899
负责人：
Janghoo Lim
金额：
$ 68.62万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10390899
关键词：
Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyotrophic Lateral Sclerosis Autopsy Behavioral Biochemical Biological Assay CAG repeat Cell Differentiation process Cell Line Cell Lineage Cells Cerebellar Ataxia Cerebellum Code Codon Nucleotides Complex DNA Sequence Alteration Data Dependence Disease Disease Progression Event Exons Frontotemporal Dementia Functional disorder Gene Expression Goals Histologic Human Impairment In Vitro Interruption Investigation Knock-in Mouse Knockout Mice Length Modeling Molecular Multiple Sclerosis Mus Mutation Myelin Nerve Degeneration Nervous system structure Neuraxis Neurodegenerative Disorders Neuronal Dysfunction Neurons Oligodendroglia Onset of illness Pathogenesis Pathologic Phenotype Population Process Progressive Nonfluent Aphasias Proteins Purkinje Cells Research Risk Role Sampling Single Nucleotide Polymorphism Small Nuclear RNA Therapeutic Therapeutic Intervention Time Tissues Trinucleotide Repeat Expansion Type 1 Spinocerebellar Ataxia ataxin-1 behavioral impairment cell type cohort frontotemporal lobar dementia-amyotrophic lateral sclerosis genetic approach high standard human tissue in vivo induced pluripotent stem cell insight loss of function mouse genetics mutant myelination neuron loss novel oligodendrocyte lineage oligodendrocyte progenitor polyglutamine selective expression sporadic amyotrophic lateral sclerosis stem cells transcription factor

项目摘要

Genetic mutations in ATXN1, which encodes ataxin-1 protein, have been implicated in several distinct neurodegenerative diseases. In humans, wild-type ATXN1 alleles normally contain between 4-36 consecutive CAG codons in the polyglutamine tract of the first coding exon, with those containing greater than 21 repeats typically also carrying 1 to 3 interrupting CAT codons. The expansion of the repeat tract of one ATXN1 allele to 39 or more uninterrupted repeats results in the highly penetrant, late-onset, and progressive cerebellar ataxia called spinocerebellar ataxia type 1 (SCA1). Interestingly, intermediate length expansions of ATXN1 are associated with an increased risk for developing sporadic amyotrophic lateral sclerosis and a form of frontotemporal dementia (FTD) called progressive nonfluent aphasia (PNFA), while intronic mutations that decrease ATXN1 levels also increase risk for Alzheimer’s disease (AD) and multiple sclerosis. Although ATXN1 is ubiquitously expressed in many different cell types throughout the central nervous system, most studies have primarily focused on the role of mutant ataxin-1 in the cerebellar Purkinje cells (PCs), the most obvious population of neurons to degenerate in SCA1. Therefore, the functions of ataxin-1 and the effects of different ataxin-1 mutations in other populations beyond PCs are not well-known. Furthermore, effective disease-modifying therapies for any of these neurodegenerative disorders associated with ATXN1 mutations, including SCA1, FTD, and AD, are extremely limited or non-existent. Recently, we have identified profound alterations in oligodendrocyte progenitor cells (OPCs) and oligodendrocytes (OLs) at early stages of SCA1 mice, which emerge around the onset of behavioral impairments and much earlier than PC degeneration. In this proposal, we plan to determine the precise impact of oligodendroglial deficits on neurodegenerative diseases, and to elucidate the mechanisms through which mutant and wild-type ataxin-1 regulate oligodendroglial differentiation and function. Aim 1 will employ conditional mouse genetic approaches to determine the degree to which oligodendroglial dysfunction contributes to different disease-related phenotypes using SCA1 as a model. Aim 2 will determine the cellular and molecular mechanisms through which ataxin-1 regulates oligodendroglial differentiation and function in the nervous system using in vivo and in vitro approaches. Aim 3 will expand the scope of the proposed study to human tissues and cells to examine oligodendroglial phenotypes. We anticipate that the research aims will provide fundamental insights into the role of oligodendroglia in neurodegenerative disease pathogenesis and progression, and uncover new mechanisms through which OPC differentiation into OLs is regulated. If successful, these studies will advance the importance of examining non-neuronal contributions to neurodegenerative diseases and reveal novel potential entry points for therapeutic intervention in disorders in which ATXN1 mutations are associated, including SCA1, FTD, and AD.

编码 ataxin-1 蛋白的 ATXN1 基因突变与多种不同的疾病有关在人类中，野生型 ATXN1 等位基因通常包含 4-36 个连续的。第一个编码外显子的聚谷氨酰胺束中的 CAG 密码子，其中包含超过 21 个重复通常还携带 1 至 3 个中断 CAT 密码子一个 ATXN1 等位基因的重复序列的扩展。 39 次或更多不间断重复导致高度渗透性、迟发性和进行性小脑性共济失调称为脊髓小脑性共济失调 1 型 (SCA1)，ATXN1 的暗示性中等长度扩展。与发生散发性肌萎缩侧索硬化症和某种形式的风险增加有关额颞叶痴呆 (FTD) 称为进行性非流利性失语症 (PNFA)，而内含子突变则导致降低 ATXN1 水平也会增加阿尔茨海默病 (AD) 和多发性硬化症的风险。在整个中枢神经系统的许多不同细胞类型中普遍表达，大多数研究表明主要关注突变ataxin-1在小脑浦肯野细胞（PC）中的作用，这是最明显的群体 SCA1 中神经元退化因此，ataxin-1 的功能以及不同 ataxin-1 的作用。此外，PC 以外的其他人群中的突变尚不清楚。针对与 ATXN1 突变相关的任何神经退行性疾病的疗法，包括 SCA1、FTD、最近，我们发现了深刻的变化。 SCA1小鼠早期阶段的少突胶质细胞祖细胞（OPC）和少突胶质细胞（OL），出现在行为障碍发生期间，并且比 PC 退化早得多。我们计划确定少突胶质细胞缺陷对神经退行性疾病的精确影响，并阐明突变型和野生型 ataxin-1 调节少突胶质细胞分化的机制目标 1 将采用条件小鼠遗传方法来确定其程度。使用 SCA1 作为模型，少突胶质细胞功能障碍会导致不同的疾病相关表型。将确定ataxin-1调节少突胶质细胞的细胞和分子机制使用体内和体外方法研究神经系统的分化和功能。目标 3 将扩展我们预计拟议研究的范围是针对人体组织和细胞来检查少突胶质细胞表型。该研究的目的将为了解少突胶质细胞在神经退行性疾病中的作用提供基本见解疾病发病机制和进展，并揭示 OPC 分化为新机制如果成功，这些研究将提高检查非神经元的重要性。对神经退行性疾病的贡献并揭示治疗干预的新潜在切入点与 ATXN1 突变相关的疾病，包括 SCA1、FTD 和 AD。