Exploring the role of the protocadherin CELSR3 in Tourette syndrome

项目摘要/摘要 Tourette综合征(TS)是一种具有很强遗传成分的神经发育障碍，影响0.5%-1% 孩子们的生活。TS的特点是多次反复抽搐，这是严重残疾的一个来源。这个 TS的临床管理面临相当大的挑战，部分原因是所有可用的药物疗法 不是针对致病机制的，因此只有有限的疗效和显著的副作用。 了解TS的遗传基础是阐明这种疾病的原因的关键一步；然而， 直到最近，所有可用的信息都仅限于罕见的与TS有关的基因突变 家系，因此不能推广到大多数患者。然而，最近，来自大型基因的证据 TS患者尸检样本的研究和首次基因表达分析 研究发现，原钙粘附素是调节细胞间相互作用的蛋白质超家族，在TS中起着关键作用 发病机制。为了支持这些发现，最大的关于TS从头突变的完整外显子组研究 最近发现原钙粘附素编码基因CELSR3是首批高置信度TS风险基因之一。 R21提案寻求利用这些新发现，并探索CELSR3 使用携带该基因突变的转基因小鼠模型，缺乏易患TS的倾向。 在初步研究中，我们发现幼年青春期雄性和雌性CELSR3杂合子小鼠表现出 TS样表型，包括抽动样定型和感觉运动门控缺陷，与他们的 野生型产仔仔。此外，以前的实验表明，CELSR3在中间神经元中起着关键作用 迁移和多巴胺能投射的组织。基于这一背景，我们假设 部分CELSR3缺乏导致TS相关神经行为缺陷，其机制是损害组织结构和 纹状体的分子组织。为了验证这一假设，此应用程序的两个目标将分别为： 1)绘制CELSR3杂合子小鼠的行为损害轨迹；以及2)确定 这些突变体的纹状体的组织结构和转录改变。 拟议的探索性研究将首次阐明原钙粘附素在TS个体发生和发育中的作用。 根据高危易感基因验证第一个TS模型。这些结果可能会导致 识别与TS病因学相关的新的致病过程和特定的分子途径。我们的 结果将导致未来更大规模的研究，旨在分析TS早期神经发育原因和 设计具有更好疗效、耐受性和安全性的新型特效药物疗法。

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.