Polyglutamine expansion and neuropathology

描述(由申请人提供)：有九种遗传性神经退行性疾病是由与各种疾病相关的蛋白质中的多谷氨酰胺(PolyQ)结构域扩大引起的，包括亨廷顿病(HD)和几种脊髓小脑性共济失调(SCA)疾病。尽管所有的多Q疾病蛋白在大脑和身体中都广泛表达，但它们根据涉及的多Q疾病选择性地杀死不同大脑区域的神经元。了解扩展的多聚Q蛋白介导选择性神经变性的机制对于开发治疗这些多Q疾病的有效治疗策略至关重要。现在清楚的是，蛋白质环境调节多聚Q扩展的毒性，并决定多聚Q疾病中出现的选择性神经变性；然而，这种选择性神经变性的确切机制仍不清楚。显然，在我们揭示这一机制之前，我们必须首先了解PolyQ蛋白的功能。在这一应用中，我们将重点研究SCA17，以探索多Q疾病中选择性神经退行性变的问题。脊髓小脑型共济失调17型(SCA17)是由TBP中的多聚Q扩展引起的，TBP是一种TATA盒结合蛋白，对基因转录至关重要。在这个重要的转录因子中，PolyQ结构域的扩展也会导致选择性神经变性，使人联想到HD和其他PolyQ疾病。由于TBP的功能和结构得到了很好的描述，SCA17成为研究PolyQ扩展如何改变正常蛋白质功能和导致神经退化的极佳模型。我们早期的研究表明，扩展的多Q结构域可以改变TBP与DNA和转录因子的结合。在这项应用中，我们将重点研究具有扩展多Q的突变TBP如何导致大脑中选择性神经变性。我们假设，有毒形式的突变TBP在受影响的神经元中的积累可能与其他类型的细胞不同，这种差异可能导致神经元的脆弱性。为了验证这一假设，我们将使用条件性SCA17基因敲除小鼠，这些小鼠在特定类型的细胞中内源性水平表达突变TBP。具体地说，在目标1中，我们将研究条件性SCA17敲入小鼠的神经学表型，这些小鼠在不同类型的细胞中选择性地表达突变的TBP。在目标2中，我们将研究不同形式的突变TBP是否在不同类型的细胞中积累不同。在目标3中，我们将研究不同形式的突变型TBP对核转录因子和相关神经功能的影响。这些研究将使我们深入了解SCA17的发病机制，以及在PolyQ病中看到的选择性神经变性。公共卫生相关性：9种遗传性神经退行性疾病是由各种疾病蛋白中多聚谷氨酰胺(PolyQ)结构域的扩展引起的。虽然所有多Q病蛋白在大脑和身体中都广泛表达，但它们选择性地杀死每种多Q病不同大脑区域的神经元。了解扩展的多聚Q蛋白介导选择性神经退行性变的机制将极大地帮助治疗这些多Q疾病。在本应用中，我们将重点研究脊髓小脑性共济失调-17(SCA17)，以解决多Q疾病中选择性神经退行性变的问题。SCA17是由TBP中的多聚Q扩展引起的，TBP是一种普遍表达的TATA盒结合蛋白，对基因转录是必不可少的。这种功能完善的重要转录因子的多Q结构域的扩展也会导致选择性的神经变性。我们将研究在特定类型的细胞中表达突变TBP的条件性敲入SCA17小鼠，以及突变TBP在神经退化中的作用。这些研究旨在为了解多Q疾病的选择性神经变性提供洞察力，并帮助开发有效的治疗策略。

DESCRIPTION (provided by applicant): There are nine inherited neurodegenerative disorders caused by the expansion of a polyglutamine (polyQ) domain in proteins associated with various diseases, including Huntington's disease (HD) and several spinocerebellar ataxia (SCA) disorders. Although all polyQ disease proteins are widely expressed in the brain and body, they selectively kill neurons in distinct brain regions depending on the polyQ disease involved. Understanding the mechanism by which expanded polyQ-containing proteins mediate selective neurodegeneration is critical to the development of effective therapeutic strategies for treating these polyQ diseases. It is now clear that protein context modulates the toxicity of polyQ expansion and determines the selective neurodegeneration seen in polyQ diseases; however, the exact mechanism for this selective neurodegeneration remains unknown. It is apparent that before we can uncover this mechanism, we must first understand the function of the polyQ protein. In this application, we will focus on SCA17 to explore the issue of selective neurodegeneration in polyQ diseases. Spinocerebellar ataxia type 17 (SCA17) is caused by polyQ expansion in TBP, a TATA-box binding protein that is essential for gene transcription. Expansion of the polyQ domain in this important transcription factor also induces selective neurodegeneration reminiscent of HD and other polyQ diseases. As the function and structure of TBP are well characterized, SCA17 makes an excellent model for studying how polyQ expansion alters normal protein function and causes neurodegeneration. Our earlier studies have demonstrated that the expanded polyQ domain can alter the binding of TBP to DNA and transcriptional factors. In this application, we will focus on how mutant TBP with an expanded polyQ causes selective neurodegeneration in the brain. We hypothesize that the accumulation of toxic forms of mutant TBP may be different in affected neurons versus other types of cells and that this difference contributes to neuronal vulnerability. To test this hypothesis, we will use conditional SCA17 knock-in mice that express mutant TBP in selected types of cells at the endogenous level. Specifically, in Aim 1 we will examine the neurological phenotypes of conditional SCA17 knock-in mice that selectively express mutant TBP in different types of cells. In Aim 2 we will investigate whether different forms of mutant TBP accumulate differently in various types of cells. In Aim 3 we will study the effects of different forms of mutant TBP on nuclear transcription factors and related neuronal function. These studies will give us insight into the pathogenesis of SCA17 and the selective neurodegeneration seen in polyQ diseases. PUBLIC HEALTH RELEVANCE: Nine inherited neurodegenerative disorders are caused by the expansion of a polyglutamine (polyQ) domain in various disease proteins. Although all polyQ disease proteins are widely expressed in the brain and body, they selectively kill neurons in distinct brain regions in each polyQ disease. Understanding the mechanism by which expanded polyQ-containing proteins mediate selective neurodegeneration would greatly help treat these polyQ diseases. In this application, we will focus on spinocerebellar ataxia-17 (SCA17) to address the issue of selective neurodegeneration in polyQ diseases. SCA17 is caused by polyQ expansion in TBP, a TATA-box binding protein that is ubiquitously expressed and essential for gene transcription. Expansion of the polyQ domain in this important transcription factor with well-characterized function also induces selective neurodegeneration. We will investigate conditional knock-in SCA17 mice that express mutant TBP in selective types of cells and the role of mutant TBP in neurodegeneration. These studies aim to provide insight into the selective neurodegeneration in polyQ diseases and help develop effective therapeutic strategies.