Comparison of HD and HDL2 mouse models to reveal common mechanisms of pathogenesis

项目摘要 HD是一种常染色体显性遗传的神经退行性疾病，其特征在于运动、认知和 情绪紊乱，不断走向死亡目前还没有疾病修饰 HD的治疗。尽管临床抑制策略处于临床试验或临床前开发阶段， 这些治疗的有效性和耐受性仍然未知，因此非常需要研究， 对于其他治疗靶点。为了促进对治疗干预的HD途径进行优先排序， 我们已经开始努力将HD与亨廷顿病样2（HDL 2）进行比较。HDL 2，发现 由我们小组在遗传学上定义，是一种成人发病的常染色体显性神经退行性疾病， 在临床上、遗传学上和神经病理学上与HD非常相似。专家无法区分 两种疾病之间的联系这两种疾病都是由重复扩张引起的 突变; HDL 2突变是由基因中染色体16 q24上的CTG/CAG扩增引起的 嗜连接蛋白-3。像HD一样，多聚谷氨酰胺的扩展轨道可能是HDL 2的关键因素 发病机制然而，也像HD，RNA转录物含有扩展的重复序列和缺失的- 发现重复序列的基因的功能也可能导致发病。 我们假设HD和HDL 2共享致病途径，检测这些途径将 从而进一步了解这两种疾病和开发新的治疗靶点。一部分 为了验证这一假设，我们建议使用CRISPR/Cas9和ssDNA供体来产生一种新的基因。 HDL 2敲入（KI）小鼠模型，具有14个（正常）或约100个三联体（突变）。我们将比较这些 具有类似KI HD系Hdh 10/+和HDh 111/+的新小鼠系。在目标1中，我们将检验假设 通过比较HDL 2和HD扩增突变的行为和 HDL 2和HD KI系的神经病理学。在目标2中，我们将测试类似分子的假设， 机制与HD和HDL 2发病机制相关，通过使用RNAseq比较HD和HDL 2发病机制的模式， HDL 2和HD模型小鼠中的基因表达。如果成功，该项目将为以下方面提供基础： 旨在为HD和HDL 2寻找新的治疗靶点的详细研究。

Project Summary HD is an autosomal dominant neurodegenerative disease, characterized by movement, cognitive and emotional disorders, with relentless progression to death. There is currently no disease-modifying treatment for HD. Though clinical suppression strategies are in clinical trials or preclinical development, the efficacy and tolerability of these treatments remains unknown, hence there is great need to search, in parallel, for other therapeutic targets. To facilitate prioritizing HD pathways for therapeutic interventions, we have launched an effort to compare HD with Huntington’s disease-like 2 (HDL2). HDL2, discovered and genetically defined by our group, is an adult onset autosomal dominant neurodegenerative disorder that is clinically, genetically, and neuropathologically remarkably similar to HD. Experts cannot distinguish between the two disorders without genetic testing. Both disorders are caused by a repeat expansion mutation; the mutation in HDL2 is caused by a CTG/CAG expansion on chromosome 16q24 in the gene junctophilin-3. Like HD, expanded tracks of polyglutamine probably are the key factor in HDL2 pathogenesis. However, also like HD, RNA transcripts containing the expanded repeat and a loss-of- function the gene in which the repeat is found likely also contribute to pathogenesis. We hypothesize that HD and HDL2 share pathogenic pathways, and that detecting these pathways will lead to further understanding of both disorders and the development of new therapeutic targets. As part of our efforts to test this hypothesis, we propose to use CRISPR/Cas9 and ssDNA donors to generate an HDL2 knock-in (KI) mouse model with either 14 (normal) or ~100 triplets (mutation). We will compare these new mouse lines with the similar KI HD lines Hdh10/+ and HDh111/+. In Aim 1, we will test the hypothesis that the HDL2 and HD expansion mutations results in a similar phenotype by comparing the behavior and neuropathology of HDL2 and HD KI lines. In Aim 2, we will test the hypothesis that similar molecular mechanisms are associated with HD and HDL2 pathogenesis by using RNAseq to compare the pattern of gene expression in the HDL2 and HD model mice. If successful, this project will provide the basis for detailed studies designed to find new therapeutic targets for both HD and HDL2.