Validating NT17 Dependent Mechanisms in Huntington's Disease Suppression

描述（由申请人提供）：亨廷顿蛋白的前17个氨基酸（NT 17结构域）被认为是亨廷顿病（HD）中突变亨廷顿蛋白（mhtt）介导的疾病发病机制的关键调节因子。在当前的研究中，我们创建了一种新的表达全长mhtt的HD小鼠模型（BACHD-dNT 17），并表明这些小鼠表现出加速的核mhtt积累（因此支持其作为体内细胞质滞留信号的作用），并加剧了HD样疾病的发病机制，包括运动障碍和纹状体神经变性。基于这些令人兴奋的发现，我们假设NT 17结构域及其胞质相互作用物在体内预防mhtt核积累和HD样疾病发病机制中至关重要。为了验证这一假设，我们提出了以下两个目标：目标一。使用独立的转基因小鼠系来显示NT 17结构域可以在体内以polyQ长度依赖性方式防止核mhtt积累和HD样疾病发病机制。 目标二验证新型NT 17相互作用蛋白作为细胞模型中介导NT 17依赖性htt细胞质滞留的细胞质受体，以及一种这样的相互作用物Tcp 1作为体内HD发病机制的修饰剂。 我们的研究可能会提供新的治疗见解的基础上NT 17域及其相互作用的蛋白质，以改善核mhtt毒性，并防止运动障碍和神经退行性疾病的发病在HD。 公共卫生相关性：亨廷顿病（HD）是一种常见的遗传性致命性神经退行性疾病，其特征在于进行性运动、认知和精神症状。我们提出的研究是基于一个令人惊讶的发现，即突变亨廷顿蛋白（NT 17结构域）的前17个氨基酸的缺失导致加速核突变亨廷顿蛋白的积累，并触发HD样运动障碍和神经变性。阐明NT 17结构域及其分子相互作用物在小鼠遗传模型中抑制HD发病机制的确切潜在分子机制可能为HD提供新的治疗靶点。

DESCRIPTION (provided by applicant): The first 17 amino acids of huntingtin (NT17 domain) has been implicated as a critical regulator of mutant huntingtin (mhtt) mediated disease pathogenesis in Huntington's disease (HD). In the current study, we created a novel BAC mouse model of HD expressing full-length mhtt lacking this domain (BACHD-dNT17), and showed that these mice exhibit accelerated nuclear mhtt accumulation (hence supporting its role as a cytoplasmic retention signal in vivo), and exacerbate HD-like disease pathogenesis including movement disorder and striatal neurodegeneration. Based on these exciting findings, we hypothesize that the NT17 domain and its cytoplasmic interactors are critical in preventing mhtt nuclear accumulation and HD-like disease pathogenesis in vivo. To test this hypothesis, we proposed the following two Aims: Aim One. Using independent transgenic mouse lines to show the NT17 domain can prevent nuclear mhtt accumulation and HD-like disease pathogenesis in a polyQ-length dependent manner in vivo. Aim Two. Validating novel NT17 interacting proteins as cytoplasmic acceptors that mediate NT17- dependent htt cytoplasmic retention in cell models, and one such interactor, Tcp1, as modifier of HD pathogenesis in vivo. Our study may provide novel therapeutic insights based on the NT17 domain and its interacting proteins to ameliorate nuclear mhtt toxicity and prevent the onset of movement disorder and neurodegeneration in HD. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is a common inherited fatal neurodegenerative disorder that is characterized by progressive motor, cognitive, and psychiatric symptoms. Our proposed study is based on the surprising finding that deletion of the first 17 amino acids of mutant huntingtin (NT17 domain) leads to accelerated nuclear mutant huntingtin accumulation and triggers HD-like movement disorder and neurodegeneration. Elucidating the precise underlying molecular mechanisms through which the NT17 domain and its molecular interactors can suppress HD pathogenesis in mouse genetic models may provide novel therapeutic targets for HD.