权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10576381
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/10576381
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 Central Nervous System 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 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 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 single nucleus RNA-sequencing 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.

ATXN 1基因突变编码共济失调蛋白-ATXN 1蛋白，与几种不同的在人类中，野生型ATXN 1等位基因通常含有4- 1036个连续的 CAG密码子位于第一个编码外显子的多聚谷氨酰胺区，其中含有大于21个重复序列通常还携带1至3个中断CAT密码子。 39个或更多不间断重复导致高度渗透性、迟发性和进行性小脑共济失调脊髓小脑性共济失调1型（SCA 1）。有趣的是，ATXN 1的中间长度扩展是与患散发性肌萎缩侧索硬化症和一种形式的肌萎缩侧索硬化症的风险增加有关额颞叶痴呆（FTD）称为进行性非流利性失语（PNFA），而内含子突变，降低ATXN 1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类型的细胞中普遍表达，大多数研究表明，主要集中在小脑浦肯野细胞（PC）中的突变型共济失调蛋白-1的作用，因此，ataxin-1的功能以及不同ataxin-1对SCA 1神经元变性的影响尚需进一步研究。在PC以外的其他人群中的突变并不广为人知。此外，用于任何这些与ATXN 1突变相关的神经退行性疾病的疗法，包括SCA 1，FTD，和AD，是非常有限的或不存在的。最近，我们已经确定了深刻的变化，少突胶质细胞祖细胞（OPC）和少突胶质细胞（OL）在SCA 1小鼠的早期阶段，出现在行为障碍的发病前后，比PC退化早得多。在这个提议中，我们计划确定少突胶质细胞缺陷对神经退行性疾病的确切影响，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的1将采用条件小鼠遗传学方法来确定以SCA 1为模型研究少突胶质细胞功能障碍导致不同的疾病相关表型将确定共济失调蛋白-β 1调节少突胶质细胞的细胞和分子机制，在神经系统中使用体内和体外方法的分化和功能。目的3将扩大本研究的范围包括人类组织和细胞，以检查少突胶质细胞的表型。这项研究的目的将为少突胶质细胞在神经退行性疾病中的作用提供基本的见解。疾病的发病机制和进展，并揭示新的机制，通过OPC分化为如果成功的话，这些研究将推进检查非神经元的重要性，对神经退行性疾病的贡献，并揭示了治疗干预的新的潜在切入点与ATXN 1突变相关的疾病，包括SCA 1、FTD和AD。