Polyglutamine expansion and neuropathology

描述（由申请人提供）：有九种遗传性神经变性疾病，由与各种疾病相关的蛋白质中的多聚谷氨酰胺（polyQ）结构域的扩增引起，包括亨廷顿病（HD）和几种脊髓小脑共济失调（SCA）疾病。尽管所有polyQ疾病蛋白在大脑和身体中广泛表达，但它们根据所涉及的polyQ疾病选择性地杀死不同大脑区域中的神经元。了解扩展的含polyQ蛋白介导选择性神经变性的机制对于开发治疗这些polyQ疾病的有效治疗策略至关重要。现在很清楚，蛋白质环境调节polyQ扩增的毒性，并决定了polyQ疾病中观察到的选择性神经变性;然而，这种选择性神经变性的确切机制仍然未知。很明显，在我们发现这种机制之前，我们必须首先了解polyQ蛋白的功能。在本申请中，我们将重点关注SCA 17，以探索polyQ疾病中的选择性神经变性问题。脊髓小脑性共济失调17型（SCA 17）是由TBP中的polyQ扩增引起的，TBP是一种对基因转录至关重要的TATA盒结合蛋白。在这个重要的转录因子中polyQ结构域的扩展也诱导选择性神经变性，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表征，SCA 17成为研究polyQ扩增如何改变正常蛋白质功能并导致神经退行性变的极好模型。我们早期的研究表明，扩大polyQ结构域可以改变TBP与DNA和转录因子的结合。在本申请中，我们将重点关注具有扩展polyQ的突变TBP如何导致大脑中的选择性神经变性。我们推测，与其他类型的细胞相比，受影响的神经元中毒性形式的突变TBP的积累可能是不同的，这种差异有助于神经元的脆弱性。为了检验这一假设，我们将使用条件性SCA 17敲入小鼠，其在内源性水平上在选定类型的细胞中表达突变TBP。具体而言，在目标1中，我们将检查在不同类型的细胞中选择性表达突变TBP的条件性SCA 17敲入小鼠的神经学表型。在目标2中，我们将研究不同形式的突变TBP是否在各种类型的细胞中积累不同。目的3：研究不同形式的TBP突变体对核转录因子及相关神经元功能的影响。这些研究将使我们深入了解SCA 17的发病机制和polyQ疾病中观察到的选择性神经变性。

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.