AD易感基因RPL13的作用机制研究

Alzheimer’s disease (AD) is a neurodegenerative disorder with a clinical manifestation of cognitive and memory function damage. Insights into the mechanisms of the progression of AD are needed to develop new drug and therapeutic treatments for AD. So far, there is few effective drugs to prevent the aggravation due to elusive pathogenesis of AD. In our recent (unpublished) study, we found that Ribosome protein L13 (RPL13) could be considered as an AD susceptibility gene. Gene expression analysis in AD using the Gene Expression Omnibus (GEO) database showed that RPL13 mRNA is highly expressed in the hippocampus of AD patients and entorhinal cortex neurons containing neurofibrillary (which is typical of AD pathology). Genetic association analyses based on 1633 AD samples showed that single nucleotide polymorphism (SNP) rs3211567 in the RPL13 gene conferred AD genetic susceptibility. Moreover, expression Quantitative Trait Locai data indicated that risk genotype TT of rs3211567 was significantly associated with a reduced RPL13 mRNA level. In this study, we aim to further characterize the roles of RPL13 in AD pathogenesis. We will (1) elucidate the regulation of RPL13 expression at the genetic level and define the relationship between expression quantity of RPL13 and the progression of AD; (2) define the roles of RPL13 in the regulation of apoptosis and function of neurons; (3) identify new factor(s) regulating in the progression of AD through RPL13 pathway. Our results will uncover the mechanism of the RPL13 gene during the progression of AD, and will (potentially) help with the therapeutic interventions of AD.

阿尔兹海默症（AD）是临床表现为认知和记忆功能损伤的神经退行性疾病。AD的发病机理存在多种假说，但具体机制至今未明，目前尚无控制AD发展进程的药物和治疗方法。因此，深入研究AD发生发展的分子机制是新药开发和疾病诊治的基础。我们基于现有数据库数据挖掘分析和功能实验发现，核糖体蛋白L13（RPL13）在AD患者海马和有神经纤维缠结（AD显著病理特征之一）的神经元中高表达； RPL13单核苷酸多态位点rs3211567与AD发病显著相关，且风险基因型TT显著降低大脑组织中的该基因表达水平。本项目拟在此基础上，进一步明确RPL13表达水平的调控及RPL13表达量与AD发生的关系，分析RPL13对神经元凋亡的调控，并鉴定出与RPL13相互作用的蛋白，阐明RPL13的信号通路作用机制。通过以上研究，深入探讨RPL13与AD发生发展的分子机制，为AD临床诊治提供新的视角。

阿尔兹海默症（AD）是临床表现为认知和记忆功能损伤的神经退行性疾病。AD的发病机理存在多种假说，但具体机制至今未明，目前尚无控制AD发展进程的药物和治疗方法。因此，深入研究AD发生发展的分子机制是新药开发和疾病诊断的基础。我们整合了AD病人表观基因组学、基因组学以及转录组学的数据，发现受表观遗传和风险等位基因的调控，RPL13在AD病人中低水平表达。进一步的机制研究表明，RPL13的敲降导致了RPL5及RPL11的转位并与P53竞争性结合其泛素化蛋白MDM2，从而稳定P53并使P53在细胞中累积。转录因子P53的累积增强PSEN2，PEN-2，P-GSK3b及Bax等基因的表达，这些基因相应地引起Abeta剪切增多，Tau磷酸化增加及神经元凋亡等AD相关生化指标的出现。我们的研究结果提示RPL13的表达量下降介导的P53信号通路激活可能是AD发生发展的原因，这为AD临床诊治提供了新的视角。同时，我们发现的抑癌基因P53在AD病人中的累积及调控作用可能部分解释了AD与癌症相反的发病率。