Brain: HSPA2被确定为晚发型阿尔兹海默症的一个关键驱动因子

蛋白质是人类表型的主要效应物（effectors），因此在基因变异和转录表达的背景下去理解蛋白质的表达是至关重要的。到目前为止，已经在人类、酵母菌和啮齿动物中成功完成了将蛋白质组数据整合到生物网络分析中的工作【1-3】。大多数人类数据源于淋巴母细胞（lymphoblasts），然而这些细胞极易产生新的变异【3】。尤其是，在淋巴母细胞中发现的许多靶标不能在脑组织中进行复制。所以这种基于细胞的研究体系并不适合于构建人类疾病模型【4】。

2018年8月20日，来自美国太平洋西北国家实验室、美国西奈山伊坎医学院、美国迈阿密大学米勒医学院、美国内布拉斯加大学林肯分校、美国哥伦比亚大学医学中心、英国纽卡斯尔大学、西班牙巴塞罗那大学等十多家研究单位组成的研究团队，将他们的一篇突破性研究成果以The human brainome: network analysis identifies HSPA2 as a novel Alzheimer’s disease target为题发表在Brain上。

研究表明：基因和蛋白表达的改变对于研究晚发型阿尔兹海默症（AD）是至关重要的，HSPA2（heat shock protein family A member 2，热休克蛋白家族成员2）被证实为晚发型AD过程中的一个特异性关键调控因子【5】。

在此之前，研究者们已经阐明了DNA等位基因如何调控RNA转录的下游表达，以及这些关联性在晚发性AD中是如何发生变化的【6-7】。

在本研究中，研究者们将继续阐明在不同的两个体系中，蛋白质是如何被整合到网络中的，同时，将在不同的两种细胞系中对结果做进一步的评估。

研究技术路线包括：（i）数量性状基因座的表达预测；（ii）差异性表达的确定；（iii）转录和肽关系的网络分析；（iv）在两种不同细胞系中的效应评估(Fig.1)。

Fig.1 Analysis pipeline: A summary of the steps that were taken on the processed data is shown. Round rectangles indicate input data, green round rectangles indicate input data from external sources, and orange squares indicate processes and outputs from those processes. Steps are numbered on the figure. See main text for further detail. BN = Bayesaian network; DBs = databases; DE = differential expression; eQTL = expression quantitative trait loci; GO = Gene Ontology database; mSig = Molecular Signatures Database; WGCNA = weighted correlation network analysis.

总而言之，通过无假设的研究方法（hypothesis-free approach），研究者们绘制（map：确定基因在染色体中的位置）并验证了6种新的靶标，以揭示在晚发型AD患者中DNA、RNA和蛋白质关系中的错误调控。

这6种新靶标分别是：HSPA2、RGS4（regulator of G-protein signaling-4，G-蛋白信号转导调节子4）、CCT5（为T-复合物多肽1（T-complex polypeptide 1，TCP1）成员，TCP1是近些年新发现的分子伴侣家族）、GNA12（属于GPCR体系，GPCR即G蛋白偶联受体）、PDHB（属于丙酮酸脱氢酶（Pyruvate dehydrogenase，PDH），PDH是一种核编码的线粒体多酶复合物，它催化丙酮酸转化为乙酰辅酶和二氧化碳，并提供糖酵解和三羧酸循环之间的主要连接）、COMT（属于主要的儿茶醇胺降解酶，突触间隙吸收后在神经元和微神经胶质细胞中发挥作用）(Table.1)。

发现在这6种靶标中有多个靶标能够在两个不同的神经病理学数据集之间进行复制。在两种不同细胞系独立实验和靶标个体转导独立实验中，特定靶标对β₄₀-淀粉样蛋白、β₄₂-淀粉样蛋白、tau蛋白或p-tau蛋白（磷酸化微管相关蛋白tau）具有一定的影响，因此确定了晚发型AD的发病途径及因果关系(Fig. 2)。

Fig. 4  Key driver analysis: (A) Transcripts. Shown is the graph counting the significant over-representation of particular key drivers in the  networks using the transcript dataset as the projection series. (B) Peptides. Shown is the graph counting the significant over-representation of particular key drivers in the networks using the peptide dataset as the projection series.

尽管，研究表明这6种靶标与晚发型AD有着密切关联（包括伴侣蛋白复合物、线粒体改变、或GPCR信号通路的晚发型AD的影响），但是许多靶标并没有在晚发型AD的背景下被进行研究。

在6种靶标中，发现HSPA2显示出最匹配的结果，且对晚发型AD的影响最为显著：即对β-淀粉样蛋白和tau蛋白的表达水平的影响最为显著，所以最终确定HSPA2为晚发型AD的一种关键驱动因子(Fig.3-4)。

Fig. 3  HSPA2 APP measures. 

Fig. 4  HSPA2 tau measures. Shown in the figure are the levels of total RNA.

补充阅读

---

文献参考

【1】Portelli MA, et al. Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels. FASEB J 2014; 28: 923–34.

【2】Wu G, Nie L, Zhang W. Integrative analyses of posttranscriptional regulation in the yeast Saccharomyces cerevisiae using transcriptomic and proteomic data. Curr Microbiol 2008; 57: 18–22.

【3】Stark AL, et al. Protein quantitative trait loci identify novel candidates modulating cellular response to chemotherapy. PLoS Genet 2014; 10:e1004192.

【4】Hong MG, Myers AJ, Magnusson PK, Prince JA. Transcriptome-wide assessment of human brain and lymphocyte senescence. PLoS One 2008; 3: e3024.

【5】Vladislav A Petyuk, et al. The human brainome: network analysis identifies HSPA2 as a novel Alzheimer’s disease target, Brain, 2018;141:2721–2739.

【6】Myers AJ. AD gene 3-D: moving past single layer genetic information to map novel loci involved in Alzheimer’s disease. J Alzheimers Dis 2013; 33 (Suppl 1): S15–22.

【7】Myers AJ. The genetics of gene expression: multiple layers and multiple players. In: Coppola G, editor. The OMICs: applications in neuroscience. New York, NY: Oxford University Press; 2014. p. 132–52.

---

通讯作者简介

Amanda J. Myers  PhD

• Assistant Professor Translational Research

 [e-mail]

Lab: http://labs.med.miami.edu/myers/LFuN/LFUN/INDEX-2.html

Dr. Amanda J. Myers has been at the University of Miami since 2007. She graduated from the University of Pennsylvania and performed work there mapping the connections of retina midget and bipolar cells as well as mapping dopaminergic pathways in the midbrains of Parkinson’s and Alzheimer’s disease subjects. Her PhD was obtained from Washington University in St Louis in 2002. She had a resident research associateship through the National Academy of Sciences to perform her postdoctoral work at the National Institute on Aging. There she began her work mapping the relationship between DNA alleles and RNA profiles and how those relationships are changed in Alzheimer’s disease. In 2007, she obtained a tenure-track post at the University of Miami and was tenured in 2014. She has co-appointments in the Division of Neuroscience, the Department of Human Genetics and Genomics, and the Center on Aging and is a founding member of the Academy of Medical Educators. Dr. Myers is currently interested in furthering the capture of ‘omics targets in human brain tissues, novel analysis methods for capturing genomic control of expression, as well as targeting best practice methods for following de novo hits from her screens.

---

任何公众平台、媒体转载使用须经授权，同时须文首注明原文来源：逻辑神经科学 （ID：LT-Neuroscience）及文末添加：平台二维码；投稿、合作、转载授权等事宜请联系微信ID：

Wang-Sizhen 或邮箱：[e-mail]

---

关注 逻辑神经科学 微信公众号

添加管理员微信号，带你入坑（入群）

微博账号（逻辑神经科学LT-Neurosci）