Exploring the role of the protocadherin CELSR3 in Tourette syndrome

项目总结/摘要 抽动秽语综合征（TS）是一种神经发育障碍，具有很强的遗传成分，影响0.5-1% 孩子们。TS的特征是多发性、复发性抽搐，这是严重残疾的来源。的 TS的临床管理带来了相当大的挑战，部分原因是所有可用的药物治疗 对致病机制没有特异性，因此仅具有有限的功效和显著的副作用。 了解TS的遗传基础是阐明这种疾病原因的重要步骤;然而， 直到最近，所有可用的信息都仅限于与TS零星相关的罕见基因突变 家系，因此不能推广到大多数患者。然而，最近，来自大型基因组的证据表明， 研究和第一个基因表达分析的死后样本从TS影响的个人， 显示原钙粘蛋白，一个调节细胞间相互作用的蛋白质超家族，在TS中起关键作用 发病机制为了支持这些发现，最大的TS从头突变的全外显子组研究 最近鉴定了原钙粘蛋白编码基因CELSR 3作为第一个高置信度TS风险基因之一。 这项R21提案旨在利用这些新发现并探索CELSR 3 缺乏易患TS，使用携带该基因突变的转基因小鼠模型。 在初步研究中，我们发现青春期前后的雄性和雌性CELSR 3杂合子小鼠表现出 TS样表型，包括抽动样刻板印象和感觉运动门控缺陷，与其相比 野生型同窝仔。此外，先前的实验表明，CELSR 3在中间神经元中具有关键作用， 迁移和多巴胺能投射的组织。基于这一背景，我们假设， 部分CELSR 3缺陷通过损害组织结构和神经功能， 纹状体的分子结构为了检验这一假设，本申请的两个目的将分别是： 1)绘制CELSR 3杂合小鼠的行为障碍的轨迹;和2）确定 这些突变体的纹状体的组织结构和转录组学改变。 这些探索性研究将首次阐明原钙粘蛋白在TS个体发育中的作用， 验证基于高风险脆弱性基因的TS的第一模型。这些结果可能会导致 鉴定新的致病过程和参与TS病因学的特定分子途径。我们 结果将导致未来更大规模的研究，旨在分析TS的早期神经发育原因， 设计具有更好疗效、耐受性和安全性的新型特定药物疗法。

PROJECT SUMMARY / ABSTRACT Tourette syndrome (TS) is a neurodevelopmental disorder with a strong genetic component, affecting 0.5-1% of children. TS is characterized by multiple, recurring tics, which are a source of significant disability. The clinical management of TS poses considerable challenges, partially because all available pharmacotherapies are not specific to the pathogenic mechanisms, and thus have only limited efficacy and significant side effects. Understanding the genetic basis of TS is an essential step to elucidate the causes of this disorder; however, until recently, all available information was limited to rare genetic mutations sporadically associated with TS pedigrees, and thus could not be generalized to most patients. Recently, however, evidence from large genetic studies and the first gene-expression analyses of postmortem samples from TS-affected individuals has revealed that protocadherins, a superfamily of proteins regulating cell-cell interactions, play a key role in TS pathogenesis. In support of these findings, the largest whole-exome studies on de novo mutations in TS recently identified the protocadherin-encoding gene CELSR3 as one of the first high-confidence TS risk genes. This R21 proposal seeks to leverage these new discoveries and explore the mechanisms whereby CELSR3 deficiency predisposes to TS, using transgenic mouse models harboring a mutation of this gene. In preliminary studies, we found that juvenile peripubertal male and female CELSR3 heterozygous mice exhibit TS-like phenotypes, including tic-like stereotypies and sensorimotor gating deficits, in comparison with their wild-type littermates. Furthermore, previous experiments showed that CELSR3 has a critical role in interneuron migration and the organization of dopaminergic projections. Based on this background, we hypothesize that partial CELSR3 deficiency leads to TS-related neurobehavioral deficits by impairing the histoarchitectural and molecular organization of the striatum. To test this hypothesis, the two aims of this application will respectively: 1) chart the trajectory of the behavioral impairments of CELSR3 heterozygous mice; and 2) determine the histoarchitectural and transcriptomic alterations of the striatum of these mutants. The proposed exploratory studies will be the first to elucidate the role of protocadherins in TS ontogeny and validate the first model of TS based on a high-risk vulnerability gene. These results are likely to lead to the identification of novel pathogenic processes and specific molecular pathways involved in TS etiology. Our results will lead to future larger studies aimed at the analysis of early neurodevelopmental causes of TS and the design of novel specific pharmacotherapies with better efficacy, tolerability, and safety profiles.