Investigating selective regional and neuronal disease vulnerability in Spinocerebellar Ataxia Type 2

调查 2 型脊髓小脑共济失调的选择性区域和神经元疾病脆弱性

基本信息

  • 批准号:
    10495190
  • 负责人:
  • 金额:
    $ 4.68万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY: Neurodegenerative disorders manifest selectively in particular neuronal populations and brain regions, through mechanisms we do not yet understand. Spinocerebellar Ataxia Type 2 (SCA2) is a fatal, hereditary neurodegenerative disorder caused by expansions in the CAG nucleotide repeat region of the ATXN2 gene, causing a gain-of-function ATXN2 protein with neurotoxic properties. While ATXN2 is expressed throughout the CNS, only a subset of brain structures and neurons are vulnerable to gross atrophy and cell death. The cerebellum is highly affected, resulting in the loss of voluntary movement, motor coordination, and speech difficulties in SCA2 patients. Across disease progression, there is pronounced cerebellar degeneration and selective loss of cerebellar Purkinje cells. Cerebellar degeneration occurs anterior to posterior, with the most posterior regions resistant to neurodegeneration. Multiple genetic and environmental insults also cause anterior to posterior cerebellar atrophy, suggesting that a conserved mechanism underlies the neurodegeneration gradient. To date, the cellular and molecular mechanisms underlying the variable cerebellar and Purkinje cell- specific vulnerability in SCA2 have not been investigated. I hypothesize that regional cerebellar vulnerability in SCA2 is modified by differential expression of neuroprotective pathways in response to cellular stress and disease. I will address this hypothesis in the following specific aims. In Aim 1, I will test whether Hspb1, a gene enriched in the posterior cerebellum, and previously identified as neuroprotective in other cerebellar degenerative disorders, can contribute to the protection of Purkinje cell loss in a mouse model of SCA2. If so, this will further support a conserved mechanism underlying the degenerative pattern and suggest common therapeutic avenues. In Aim 2A, I will identify novel neuroprotective pathways in a SCA2 model with the use of high throughput single-cell RNA-sequencing of the cerebellar transcriptome at fine temporal and spatial resolution. In Aim 2B, I will specifically address regional Purkinje cell vulnerability in SCA2 through the use of cell-type-specific ribosomal profiling to assess differential gene expression between disease-vulnerable and - resilient Purkinje cell populations. By comparing differential gene expression between the anterior and posterior cerebellum in both Aim 2A and Aim 2B, I will identify novel genetic modifiers of disease vulnerability for future validation. This study will be the first to characterize SCA2 degeneration and disease progression at a single- cell spatiotemporal resolution. As there is no effective treatment available for SCA2 patients, understanding the factors that protect against neurodegeneration and cell-type-specific contributions to disease pathology will help to better inform future therapeutic interventions.
项目概要: 神经退行性疾病通过以下途径选择性地表现在特定的神经元群体和脑区域中: 我们还不了解的机制。脊髓小脑共济失调2型(SCA 2)是一种致命的,遗传性 由ATXN 2基因的CAG核苷酸重复区的扩增引起的神经变性疾病, 导致具有神经毒性特性的功能获得性ATXN 2蛋白。虽然ATXN 2在整个细胞中表达, CNS,仅是脑结构和神经元的一个子集,易受严重萎缩和细胞死亡的影响。的 小脑受到严重影响,导致自主运动、运动协调和言语的丧失 SCA 2患者的困难。在疾病进展过程中,有明显的小脑变性, 小脑浦肯野细胞的选择性丧失。小脑变性发生在前向后, 后部区域抵抗神经变性。多种遗传和环境的损伤也会导致前 小脑后部萎缩,这表明一个保守的机制是神经变性的基础。 梯度离心迄今为止,可变的小脑和浦肯野细胞的细胞和分子机制- 尚未调查SCA 2中的特定漏洞。我假设小脑的局部脆弱性 在SCA 2中,通过响应细胞应激的神经保护通路的差异表达来修饰 和疾病我将在以下具体目标中阐述这一假设。在目标1中,我将测试Hspb 1,a 在小脑后部富集的基因,先前被鉴定为在其他小脑中具有神经保护作用。 退行性疾病,可以有助于保护SCA 2小鼠模型中的浦肯野细胞损失。如果是这样的话, 这将进一步支持退行性模式下的保守机制, 治疗途径在目标2A中,我将在SCA 2模型中识别新的神经保护通路, 小脑转录组的高通量单细胞RNA测序 分辨率在目标2B中,我将通过使用以下方法来具体解决SCA 2中的区域性浦肯野细胞脆弱性: 细胞类型特异性核糖体分析,以评估疾病易感性和 弹性浦肯野细胞群。通过比较前、后牙区的基因表达差异, 在Aim 2A和Aim 2B中,我将确定疾病易感性的新遗传修饰物, 验证。这项研究将是第一个表征SCA 2变性和疾病进展的单一- 细胞时空分辨率由于没有有效的治疗方法可用于SCA 2患者,了解 防止神经变性和细胞类型特异性对疾病病理学的贡献的因素将有助于 以更好地为未来的治疗干预提供信息。

项目成果

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Ashley Brooke Robbins其他文献

Ashley Brooke Robbins的其他文献

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{{ truncateString('Ashley Brooke Robbins', 18)}}的其他基金

Investigating selective regional and neuronal disease vulnerability in Spinocerebellar Ataxia Type 2
调查 2 型脊髓小脑共济失调的选择性区域和神经元疾病脆弱性
  • 批准号:
    10231530
  • 财政年份:
    2021
  • 资助金额:
    $ 4.68万
  • 项目类别:

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