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中的遗传突变已在几种不同的神经退行性疾病。在人类中，野生型ATXN1等位基因通常连续4-36个第一个编码外显子的聚谷氨酰胺道中的CAG密码子，其中包含大于21重复通常还携带1到3个中断猫密码子。一个ATXN1等位基因的重复道扩展到 39个或更多不间断的重复会导致高度渗透，迟到和进行性小脑共济失调称为1型脊髓脑性共济失调（SCA1）。有趣的是，ATXN1的中间长度扩展为与增加零星营养性侧硬化症的风险增加有关额颞痴呆（FTD）称为进行性非流传性失语（PNFA），而内含子突变（降低ATXN1水平还增加了阿尔茨海默氏病（AD）和多发性硬化症的风险。尽管ATXN1 在整个中枢神经系统的许多不同的细胞类型中，无处不在，大多数研究具有主要集中于突变型ataxin-1在小脑Purkinje细胞（PC）中的作用，这是最明显的种群在SCA1中退化的神经元。因此，ataxin-1的功能和不同的ataxin-1的作用除PC以外的其他人群中的突变不是众所周知的。此外，有效修改疾病与ATXN1突变有关的任何这些神经退行性疾病的疗法，包括SCA1，FTD，和AD，非常有限或不存在。最近，我们确定了在SCA1小鼠的早期阶段，少突胶质细胞祖细胞（OPC）和少突胶质细胞（OLS）围绕行为障碍的发作，比PC变性早得多。在此提案中，我们计划确定寡头缺陷对神经退行性疾病的精确影响，并确定对神经退行性疾病的影响阐明突变体和野生型ataxin-1调节寡头分化的机制和功能。 AIM 1将采用有条件的小鼠遗传方法来确定使用SCA1作为模型有助于不同的与疾病相关的表型。目标2 将确定actaxin-1调节寡头的细胞和分子机制使用体内和体外方法在神经系统中的分化和功能。 AIM 3将扩展拟议的研究范围对人体组织和细胞检查橄榄膜表型。我们期待该研究的目的将提供对寡聚胶质中的作用在神经退行性中的作用的基本见解。疾病的发病机理和进展，并发现了新机制，OPC分化为 OLS受调节。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，并揭示了热干预的新型潜在入口点在与ATXN1突变相关联的疾病中，包括SCA1，FTD和AD。