类朊蛋白"Sho"调控抑郁作用的研究

Sho, a paralogue of prion protein discovered in recent years, is probably an important co-factor in prion disease pathogenesis. Further study for the Sho protein will give us a new hope to understand the mechanism of prion pathogenesis. In our preliminary study, two mouse models, the Sho gene overexpression or knock out models, were undergone depression behaviour tests such as force swimming test (FST) and tail suspension test. These studies suggested that Sho may have an effect on the regulation of depression. In this proposal study, we will further analyse the hippocampus neuronal regeneration, the structure of hippocampus, and the morphology of hippocampus neurons in mouse models of both Sho gene overexpression and Sho gene knock out. Meanwhile, by using LC-MS/MS, proteomics techniques and knowledge based bioinfomatics methods, we will study and analyse the effect of Sho on the mechanism of molecular regulation of depression. This study will provide the foundation of understanding the mechanism of prion pathogenesis, and the explanation of why patients with prion disease show depression syndrome. Furthermore, this study will also provide a new drug target for the treatment of human depression syndrome.

近几年新发现的类朊蛋白-Sho，可能是朊病毒致病的一个重要协助因子，它给朊病毒病发病机理研究带来新的希望，迫切需要人们对Sho开展相关研究。课题组前期通过已建立的Sho高表达和基因敲除两种小鼠模型进行强迫游泳、悬尾等抑郁性行为学研究发现，Sho具有调控抑郁的作用。本项目拟继续以Sho两种模型小鼠为基础，进一步分析Sho高表达和缺失对小鼠海马神经元再生、海马结构、海马神经元形态等的影响，同时，结合LC-MS/MS等蛋白质组学技术及生物信息学知识，分析Sho调控抑郁作用的分子机制。本项目的研究将为理解朊病毒病发病机理及朊病毒病患者抑郁的临床症状提供新的理论依据，同时，也为人类抑郁症治疗提供一个新的潜在药物靶标。

类朊蛋白Shadoo是一种与朊蛋白类似的蛋白，编码基因为Sprn，Shadoo蛋白具有与朊蛋白类似的神经保护作用，参与调节多种神经生理生化过程，对于神经系统功能的调节具有重要作用。本研究以Sprn基因敲除小鼠为模型，研究Shadoo蛋白对抑郁的调节作用，本课题成功筛选出Sprn基因敲除纯合小鼠，神经行为学实验证实Shadoo蛋白缺失导致小鼠出现明显抑郁及绝望行为；Sprn基因敲除小鼠海马CA1区和大脑皮层神经元密度明显小于正常野生型小鼠，Shadoo蛋白缺失导致神经元损伤或神经元再生能力下降，脑部5-羟色胺（5-HT）、多巴胺（DA）、去甲肾上腺素（NE）、脑源神经营养因子（BDNF）、IL-6、5-羟色胺受体1A（5-HTR-1A）、多巴胺受体1型（DR1）等与抑郁症相关基因表达下调。