The Regulation of Synaptic Connectivity and Homeostasis by Huntingtin

 描述（由申请人提供）：亨廷顿病（HD）是一种致命的神经退行性疾病，由在亨廷顿蛋白（Htt）的N末端引入延长的聚谷氨酰胺（poly-Q）的突变引起。一个被广泛接受但未经证实的假设是，HD是由突变Htt蛋白的功能获得性毒性作用引起的。近几 近年来，poly-Q突变的显性负性功能丧失效应也已成为疾病病理生理学的驱动因素。然而，尽管已知突变型Htt的病理生理学，野生型（WT）Htt的功能仍然在很大程度上未知。星形胶质细胞是脑的主要胶质细胞，分泌突触形成血小板反应蛋白家族蛋白以启动突触形成。血小板反应蛋白通过与神经元受体加巴喷丁受体α2δ-1结合诱导突触发生。在我们的初步实验中，我们发现α2δ-1与亨廷顿蛋白相互作用，并且这种相互作用在poly-Q扩增的存在下受损。早期的兴奋性皮质和纹状体连接的突触问题已在HD中报道，但亨廷顿蛋白是否在突触连接中发挥作用尚不清楚。通过在小鼠皮层中有条件地沉默Htt，我们发现亨廷顿蛋白控制皮层和纹状体回路内的突触形成和成熟。此外，通过使用HD小鼠模型，我们发现当存在致病性多聚谷氨酰胺突变时，亨廷顿蛋白的这种功能丧失。基于这些发现，我们将在此检验以下假设：亨廷顿蛋白通过与α2δ-1的相互作用控制突触连接，以及在存在致病性poly-Q突变的情况下这种相互作用的损害导致突触连接中的有害错误。突变型Htt在发育过程中的功能丧失效应可能对驱动疾病发作很重要，并且可能是HD前驱神经症状的基础。因此，了解WT Htt在突触发育中的功能可能使我们能够找到纠正突变亨廷顿携带者皮层和纹状体回路中发育错误的方法。因此，这种方法可以预防疾病发作或大大减少疾病进展，使HD患者能够过上充实、健康的生活。

 DESCRIPTION (provided by applicant): Huntington's disease (HD) is a fatal neurodegenerative disease caused by mutations introducing an extended stretch of poly-glutamines (poly-Q) at the N-terminus of huntingtin (Htt). A widely accepted, yet unproven, hypothesis is that HD is caused by gain-of-function, toxic effects of mutant Htt protein. In recent years, dominant negative loss-of-function effects of poly-Q mutations have also emerged as drivers of disease pathophysiology. However, despite what is known about pathophysiology of mutant Htt, the functions of wildtype (WT) Htt are still largely unknown. Astrocytes, the major glial cells of the brain, secrete synaptogenic thrombospondin family proteins to initiate synapse formation. Thrombospondin induces synaptogenesis by binding to a neuronal receptor, the gabapentin receptor α2δ-1. In our preliminary experiments, we found that α2δ-1 interacts with huntingtin and this interaction is impaired in the presence of poly-Q expansions. Early synaptic problems in the excitatory cortical and striatal connections have been reported in HD, but whether huntingtin played a role in synaptic connectivity was unknown. By conditionally silencing Htt in the mouse cortex we showed that huntingtin controls synapse formation and maturation within cortical and striatal circuits. Moreover, by using an HD mouse model, we found that this function of huntingtin is lost when the pathogenic poly-glutamine mutation is present. Based on these findings, here we will test the hypotheses that huntingtin controls synaptic connectivity through its interaction with α2δ-1, and that the impairment of this interaction in the presence of the disease-causing poly-Q mutations leads to detrimental errors in synaptic connectivity. The loss-of-function effects of mutant Htt during development may be important for driving the disease onset and could underlie prodromal neurological symptoms of HD. Therefore, understanding the function of WT Htt in synaptic development may enable us to find ways to correct the developmental errors in the cortical and striatal circuits of mutant Huntingtin carriers. This approach could therefore lead to the prevention of disease onset or greatly diminished disease progression, allowing HD patients to live full, healthy lives.