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(NT17结构域)被认为是突变的亨廷顿蛋白(MHTT)介导的亨廷顿病(HD)疾病发病的关键调节因子。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小鼠模型(BACHD-dNT17)，并表明这些小鼠表现出加速的核mHTT积聚(从而支持其在体内作为细胞质滞留信号的作用)，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因子在体内防止mHTT核积聚和HD样疾病发病中起关键作用。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显示NT17结构域可以在体内以多聚Q长度依赖的方式防止核mHTT积聚和HD样病的发病。目标二。验证新的NT17相互作用蛋白作为胞浆受体，介导依赖NT17的HTT细胞质在细胞模型中的滞留，以及一个这样的相互作用蛋白，Tcp1，作为体内HD发病的修饰物。我们的研究可能为基于NT17结构域及其相互作用蛋白的治疗提供新的见解，以改善mHTT的核毒性，防止HD运动障碍和神经变性的发生。

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.