Nuclear Toxicity of Huntington Disease Protein

亨廷顿病蛋白的核毒性

• 批准号: 8225291
• 负责人: XIAO-JIANG LI
• 金额: $ 33.55万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225291
• 关键词: Accounting; Affect; Amino Acids; Antibodies; Brain; Brain region; Cell Nucleus; Cells; Corpus striatum structure; Disease; Family; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Transcription; Huntington Disease; Inherited; Investigation; Knock-in Mouse; Length; Mediating; Mus; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Nuclear; Nuclear Proteins; Pathogenesis; Patients; Phenotype; Phosphorylation; Protein Binding; Proteins; Research; Site; Symptoms; System; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Transgenic Mice; cell type; effective therapy; human Huntingtin protein; mouse model; mutant; neuropathology; overexpression; polyglutamine; public health relevance; stem; therapy development; transcription factor

DESCRIPTION (provided by applicant): Nine inherited neurodegenerative disorders, including Huntington's disease (HD), are caused by the expansion of a polyglutamine (polyQ) domain in their associated disease proteins. A common pathological feature of these diseases is selective neurodegeneration in distinct brain regions associated with each disease, despite the widespread expression of mutant proteins throughout the brain and body. Understanding the mechanism by which expanded polyQ-containing proteins mediate selective neurodegeneration is critical for developing effective therapeutic strategies to treat these polyQ diseases. In HD patients, the selective neurodegeneration occurs first to the medium spiny neurons, which account for >90% of neurons in the striatum. In HD mice that express full-length mutant huntingtin (htt), there is a preferential accumulation of mutant htt in the nuclei of medium spiny neurons in the striatum. Since mutant htt in the nucleus interacts with transcription factors and affects gene expression, this preferential nuclear accumulation is believed to account for the selective neurodegeneration in the striatum. Understanding the mechanism for this nuclear localization will not only help elucidate the pathogenesis of HD, but also other polyQ diseases that feature nuclear accumulation and inclusions of polyQ proteins. We hypothesize that the nuclear localization of mutant htt stems from multiple factors. First, the full- length mutant htt must be degraded to generate small N-terminal htt fragments that can passively enter the nucleus to affect gene transcription. Second, cell type-specific factors can regulate the nuclear localization of mutant htt. To test these hypotheses, we will compare the subcellular distribution of full-length and N- terminal mutant htt in HD knock-in mice that express mutant htt at the endogenous level. The relationship between the nuclear accumulation of N-terminal mutant htt and neurological phenotypes or changes in gene expression will be evaluated. We will also investigate the cell type-specific toxicity of N-terminal mutant htt via the Cre-loxP system. These studies aim to test whether N-terminal mutant htt, when expressed at the endogenous level, accumulates more rapidly in the nucleus and causes more severe phenotypes than full-length mutant htt. We will also examine whether striatal neurons have specific molecules or factors that regulate N-terminal phosphorylation of mutant htt to promote its nuclear accumulation. These studies will help us develop therapies that alter htt phosphorylation to reduce the nuclear accumulation of mutant htt and its associated neuropathology. PUBLIC HEALTH RELEVANCE: Huntington disease (HD) is the most common form of polyglutamine diseases that are featured by abnormal gene expression caused by mutant proteins in the nucleus. In this application, we will use genetic mouse models of HD to investigate the mechanism by which the HD protein accumulates in neuronal nucleus. Elucidating this mechanism will help find therapeutic intervention to reduce HD neuropathology.

描述（由申请人提供）：包括亨廷顿氏病（HD）在内的九种遗传神经退行性疾病是由于其相关疾病蛋白中聚谷氨酰胺（PolyQ）结构域的扩展引起的。这些疾病的一个常见病理特征是在与每种疾病相关的不同大脑区域的选择性神经退行性特征，尽管突变蛋白在整个大脑和身体中都广泛表达。了解扩展的含PolyQ蛋白介导的选择性神经退行性的机制对于制定有效治疗这些PolyQ疾病的有效治疗策略至关重要。 在HD患者中，选择性神经退行性变性首先发生在中棘神经元中，该神经元占纹状体中> 90％的神经元。在表达全长突变体狩猎蛋白（HTT）的HD小鼠中，在纹状体中培养基神经元的核中有突变体HTT的优先积累。由于核中的突变体HTT与转录因子相互作用并影响基因表达，因此人们认为这种优先的核积累可以解释纹状体中选择性的神经变性。了解这种核定位的机制不仅将有助于阐明HD的发病机理，还将有助于其他具有核积累和PolyQ蛋白包含的PolyQ疾病。 我们假设突变htt的核定位来自多种因素。首先，必须将全长突变体HTT降解以产生小的N末端HTT片段，该片段可以被动地进入细胞核以影响基因转录。其次，细胞类型特异性因素可以调节突变体HTT的核定位。为了检验这些假设，我们将比较HD敲入小鼠中全长和N末端突变体HTT的亚细胞分布，这些小鼠在内源水平表达HTT。 N末端突变体HTT的核积累与神经表型或基因表达的变化之间的关系将得到评估。我们还将通过CRE-LoxP系统研究N末端突变体HTT的细胞类型特异性毒性。这些研究旨在测试N末端突变体HTT是否在内源水平表达时是否在细胞核中积累了更快，并导致比全长突变体HTT更严重的表型。我们还将检查纹状体神经元是否具有调节突变体HTT的N末端磷酸化以促进其核积累的特定分子或因子。这些研究将帮助我们开发改变HTT磷酸化的疗法，以减少突变体HTT及其相关神经病理学的核积累。 公共卫生相关性：亨廷顿疾病（HD）是最常见的聚谷氨酰胺疾病的形式，是由核中突变蛋白引起的异常基因表达所特征的。在此应用中，我们将使用HD的遗传小鼠模型来研究HD蛋白在神经元核中积累的机制。阐明这种机制将有助于找到治疗性干预措施，以减少HD神经病理学。