Lingo-2与Ring-1相互作用及在维持神经元存活中作用的研究

研究发现Lingo-2基因改变会增加原发性震颤及帕金森病的发生风险，目前尚无法解释基因改变导致相关疾病发生的可能机制。Lingo-2的结构与Lingo-1高度相似，提示其可能通过蛋白相互作用参与神经元的生命活动。运用酵母双杂交系统我们筛选出Lingo-2的互作蛋白Ring-1，Ring-1具有E3泛素连接酶活性，我们还发现蛋白酶体抑制剂MG132可抑制Lingo-2的降解，而神经元中过表达Lingo-2后会导致神经元的死亡。据此，推测Ring-1与Lingo-2蛋白的降解有关，影响两者相互作后可能会导致Lingo-2的异常积聚和神经元的死亡。本课题将（1）证实Lingo-2通过泛素蛋白酶系统降解；（2）证实Ring-1和Lingo-2蛋白具有相互作用；（3）了解两者相互作用对Lingo-2蛋白降解及神经元存活的影响。课题的开展将为明确相关神经系统疾病的发病机制提供实验依据。

Lingo-2, a member of LRR gene family, has been linked with Essential tremor and Parkinson's disease. The similar protein structure between Lingo-2 and Lingo-1 indicates that Lingo-2 may participate in the activities of neurons through protein-protein interaction. Recently, we identified Ring-1, a functional E3 ubiquitin ligase, as a binding partner of Lingo-2 through yeast two-hybrid screening. Furthermore, we found that the MG132, the proteosome inhibitor, blocked Lingo-2 degradation and overexpression of Lingo-2 could cause neuronal death. Based on our previous findings, we propose that Ring-1 may function as E3 ubiquitin ligase in the degradation of Lingo-2 and the disruption of the interaction between two proteins may impair the degradation of Lingo-2 and the following neuronal death. In this study，we will try to provide the direct evidence that Ring-1 is a molecule involved in the degradation of Lingo-2 which is very important for the neuronal survival. Understanding the biological function of Lingo-2 and its role in the activities of neurons will help us to explore the molecular mechanism of related neurological disorders.