The Regulation of Synaptic Connectivity and Homeostasis by Huntingtin

 描述(申请人提供)：亨廷顿病(HD)是一种致命的神经退行性疾病，由亨廷顿蛋白(Htt)的N-末端引入延伸的聚谷氨酸(Poly-Q)突变引起。一个被广泛接受但未经证实的假说是，HD是由突变的Htt蛋白的功能获得和毒性效应引起的。在最近 多年来，多聚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的病理生理机制，但野生型(Wt)Htt的功能仍在很大程度上未知。星形胶质细胞是大脑的主要神经胶质细胞，分泌突触原性凝血酶原蛋白家族蛋白启动突触形成。凝血酶原蛋白通过与神经元受体，加巴喷丁受体α2，δ-1结合来诱导突触形成。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，这种相互作用在多聚Q扩张的存在下被削弱。HD患者兴奋性皮质和纹状体连接的早期突触问题已有报道，但亨廷顿蛋白是否在突触连接中发挥作用尚不清楚。通过有条件地沉默小鼠皮质中的Htt，我们发现亨廷顿蛋白控制着皮质和纹状体回路中突触的形成和成熟。此外，通过使用HD小鼠模型，我们发现，当存在致病的聚谷氨酰胺突变时，亨廷顿蛋白的这一功能就会丢失。基于这些发现，我们将在这里测试亨廷顿蛋白通过与α2δ-1相互作用来控制突触连接的假设，以及在存在致病的PolyQ突变时这种相互作用的损害会导致突触连接中的有害错误。突变的Htt在发育过程中的功能丧失效应可能是导致疾病发生的重要原因，并可能是HD的前驱神经系统症状的基础。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Huntingtin携带者皮质和纹状体回路发育错误的方法。因此，这种方法可以预防疾病的发生或极大地减缓疾病的进展，使HD患者能够过上完整、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.