Predictive potential of circulating Ube2h mRNA as an E2 ubiquitin-conjugating enzyme for diagnosis or treatment of Alzheimer's disease

Neurodegenerative disorders are status in which neuronal cell death, miscommunications between synapse, and abnormal accumulation of proteins in the brain. Alzheimer's disease (AD) is one of the age-related disorders which is most common degenerative disorders today, and strongly involved memory consolidation and cognitive in the brain. Amyloid-ß and tau proteins are trigger for AD pathogenesis, and usually use for AD candidate biomarkers in the clinical research. Especially, clinical exam, brain imaging and molecular biological methods are being used to diagnosis for AD. Genome-wide association study (GWAS) is new biomedical method, and use contribute to understanding of many human diseases included brain diseases. Here, we identified ubiquitin conjugating enzyme E2 (Ube2) gene expression in the neuron through GWAS. The subfamilies of Ube2 genetic expression and inborn errors affect ubiquitin proteasome system (UPS) leading to protein degradation in the brain. We found that only Ube2h mRNA transcription was significantly increased in the blood from AD, however we did not find change of Ube2 subfamily genes expression in the blood and brain tissue. These data may provide information of diagnosis or clinical approach, and suggest that cell-free circulating Ube2h mRNA is novel potential biomarker for AD. Overall design: Examination of Ube2 submailies gene expression profiling from 5xFAD mouse brain and blood.

神经退行性疾病是一类以神经元死亡、突触通讯障碍及脑内蛋白质异常蓄积为特征的病理状态。阿尔茨海默病（Alzheimer's disease, AD）是当前最常见的年龄相关性退行性疾病，与大脑的记忆巩固及认知功能密切相关。β淀粉样蛋白与tau蛋白是AD发病的核心致病因素，常被用作临床研究中的AD候选生物标志物。目前用于AD诊断的手段包括临床检查、脑成像及分子生物学方法。全基因组关联研究（Genome-wide association study, GWAS）作为新兴生物医学研究方法，有助于解析包括脑部疾病在内的多种人类疾病的发病机制。本研究通过全基因组关联研究，在神经元中鉴定出泛素结合酶E2（ubiquitin conjugating enzyme E2, Ube2）的基因表达特征。Ube2亚家族的基因表达异常及先天遗传缺陷会影响泛素-蛋白酶体系统（ubiquitin proteasome system, UPS），进而干扰脑内蛋白质的正常降解过程。研究发现，仅在AD患者的血液样本中，Ube2h的mRNA转录水平显著上调；而在血液与脑组织中均未检测到Ube2其余亚家族基因表达的显著变化。本研究数据可为AD的临床诊断或诊疗策略提供参考，并提示循环游离Ube2h mRNA可作为AD的新型潜在生物标志物。实验设计：检测5xFAD小鼠脑组织与血液中的Ube2亚家族基因表达谱。