Validating NT17 Dependent Mechanisms in Huntington's Disease Suppression

描述（由申请人提供）：亨廷顿病（HD）中，亨廷顿蛋白的前17个氨基酸（NT17结构域）被认为是突变亨廷顿蛋白（mhtt）介导的疾病发病机制的关键调节因子。在本研究中，我们建立了一种新的表达缺乏该结构域的全长mhtt的BAC小鼠HD模型（BACHD-dNT17），并表明这些小鼠表现出加速的核mhtt积累（从而支持其在体内作为细胞质保留信号的作用），并加剧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NT17结构域及其细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。利用独立的转基因小鼠系显示NT17结构域可以在体内以多q长度依赖的方式阻止核mhtt积累和hd样疾病的发病。两个目标。在细胞模型中验证新的NT17相互作用蛋白作为细胞质受体介导NT17依赖的htt细胞质保留，并且其中一个相互作用蛋白Tcp1在体内作为HD发病机制的修饰剂。我们的研究可能提供基于NT17结构域及其相互作用蛋白的新的治疗见解，以改善核mhtt毒性，防止HD患者发生运动障碍和神经退行性变。

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.