Control of Excitatory Synapse Formation by Huntingtin

标题：亨廷顿蛋白对兴奋性突触形成的控制 摘要： 亨廷顿氏病（HD）是一种遗传性的、致命的神经退行性疾病， 在亨廷顿（Htt）蛋白的N-末端中的多聚谷氨酰胺（poly-Q）重复。虽然致病突变 因为HD可以在疾病发作之前很久就被检测到，目前还没有预防或延迟的治疗方法。 HD中的神经变性。Htt突变的显性性质导致了HD是由以下原因引起的假设： 突变型Htt蛋白的毒性功能获得性。因此，大多数HD治疗策略是 专注于减少或消除突变型Htt。我们实验室和其他人最近的工作表明， 另一种假设是，Htt功能的丧失也是疾病发病机制的主要驱动因素。小鼠 遗传研究，我们的实验室发现，皮质Htt是正确建立皮质和皮质- 纹状体兴奋性突触连接，并且当突变体Htt存在时，Htt的这种功能丧失。什么 野生型Htt在建立和维持突触连接中的功能？如何 野生型Htt功能的破坏有助于HD发病机制？这些问题我会 我在杜克大学的卡格拉·埃罗格鲁博士的实验室进行博士后研究时得到了答案。 在我的初步实验中，我发现了神经元Htt作为星形胶质细胞调节器的意外作用- 诱发突触发生星形胶质细胞分泌血小板反应蛋白（TSP）家族蛋白，诱导突触 通过其神经元受体加巴喷丁受体α2δ-1形成。在生化实验中，我发现 α2δ-1直接与野生型Htt相互作用，但当致病性多聚Q Htt中存在重复扩增。此外，Htt在神经元中是抑制突触发生所必需的。 TSP信号的缺乏，表明Htt和α2δ-1具有相反的功能，平衡了细胞的生长。 兴奋性突触连接基于这些发现，我提出了一个假设，即Htt是一种抑制剂， 兴奋性突触形成。我将结合原代神经元培养，分子生物学， 生物化学，共聚焦显微镜和小鼠遗传学，以检验Htt控制突触的假设。 连接通过其与α2δ-1的相互作用，并且当poly-Q 膨胀是存在的。此外，我将确定α2δ-1表达的遗传操作是否可以 在HD模型小鼠中挽救突触缺陷并延迟或停止疾病进展。总的来说，我希望这些 研究将通过以下方式确定特定的分子机制，从而显著推进HD研究领域 其野生型Htt功能的丧失有助于疾病的发病机制。此外，这些发现是 准备提供新的治疗策略，以治疗早期突触功能障碍并延迟或预防 HD中的神经变性。

Title: Control of Excitatory Synapse Formation by Huntingtin Abstract: Huntington’s Disease (HD) is an inherited, fatal neurodegenerative disease caused by an expansion of poly-glutamine (poly-Q) repeats in the N-terminus of the Huntingtin (Htt) protein. While the causative mutation for HD can be detected long before disease onset, there are currently no treatments to prevent or delay neurodegeneration in HD. The dominant nature of the Htt mutation led to the hypothesis that HD is caused by a toxic gain-of-function of the mutant Htt protein. Therefore, the majority of HD therapeutic strategies are focused on reducing or eliminating mutant Htt. Recent work from our laboratory and others suggests an alternative hypothesis, that loss of Htt function is also a major driver of disease pathogenesis. In mouse genetic studies, our lab found that cortical Htt is required for the correct establishment of cortical and cortico- striatal excitatory synaptic connections, and that this function of Htt is lost when mutant Htt is present. What are the functions of wild-type Htt in establishing and maintaining synaptic connections? How does disruption of wild-type Htt function contribute to HD pathogenesis? These are the questions that I will answer during my postdoctoral research in Dr. Cagla Eroglu’s laboratory at Duke University. In my preliminary experiments I found an unexpected role for neuronal Htt as a regulator of astrocyte- induced synaptogenesis. Astrocytes secrete thrombospondin (TSP) family proteins, which induce synapse formation via their neuronal receptor, the gabapentin receptor α2δ-1. In biochemical experiments, I found that α2δ-1 directly interacts with wildtype Htt, but this interaction is impaired when the disease-causing poly-Q repeat expansion is present in Htt. Furthermore, Htt is required in neurons to suppress synaptogenesis in the absence of TSP signaling, suggesting that Htt and α2δ-1 have opposing functions that balance the growth of excitatory synaptic connectivity. Based on these findings, I developed the hypothesis that Htt is an inhibitor of excitatory synapse formation. I will use a combination of primary neuronal culture, molecular biology, biochemistry, confocal microscopy, and mouse genetics, to test the hypothesis that Htt controls synaptic connectivity through its interaction with α2δ-1, and that this function of Htt is impaired when the poly-Q expansion is present. Additionally, I will determine whether the genetic manipulation of α2δ-1 expression can rescue synaptic deficits and delay or stop disease progression in HD model mice. Collectively, I expect these studies will significantly advance the field of HD research by identifying specific molecular mechanisms through which loss of wild-type Htt function contributes to disease pathogenesis. Furthermore, these findings are poised to provide novel therapeutic strategies to treat early synaptic dysfunction and delay or prevent onset of neurodegeneration in HD.