The human brainome: network analysis identifies HSPA2 as a novel Alzheimer’s disease target.
The human brainome: network analysis identifies HSPA2 as a novel Alzheimer’s disease target.
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DOI：
10.1093/brain/awy215
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发表时间：
2018-09-01
期刊：
影响因子：
--
通讯作者：
Myers AJ
中科院分区：
文献类型：
--
作者：
Petyuk VA;Chang R;Ramirez-Restrepo M;Beckmann ND;Henrion MYR;Piehowski PD;Zhu K;Wang S;Clarke J;Huentelman MJ;Xie F;Andreev V;Engel A;Guettoche T;Navarro L;De Jager P;Schneider JA;Morris CM;McKeith IG;Perry RH;Lovestone S;Woltjer RL;Beach TG;Sue LI;Serrano GE;Lieberman AP;Albin RL;Ferrer I;Mash DC;Hulette CM;Ervin JF;Reiman EM;Hardy JA;Bennett DA;Schadt E;Smith RD;Myers AJ
通过整合基因组、转录组和蛋白质组数据，Petyuk等人将HSPA 2鉴定为阿尔茨海默病病理学的驱动因素，在一个独立的队列中复制了这一发现，并在两个体外系统中进行了验证。这些结果突出了系统方法在识别疾病途径相关基因方面的作用。我们的假设是，基因和蛋白质表达的变化对晚发性阿尔茨海默病的发展至关重要。先前我们研究了DNA等位基因如何控制RNA转录物的下游表达，以及这些关系在晚发性阿尔茨海默病中如何改变。我们现在已经研究了蛋白质是如何在两个单独的系列中被整合到网络中的，并在两个不同的细胞系中评估了我们的输出。我们的管道包括以下步骤：（i）预测表达数量性状基因座;（ii）确定差异表达;（iii）分析转录本和肽关系的网络;以及（iv）验证两个单独细胞系中的效果。我们在两个单独的大脑系列中进行了所有分析，以验证效果。我们的两个系列包括第一组中的345个样本（177个对照，168个病例;年龄范围65 - 105; 58个女性; KRONOSII队列）和重复组中的409个样本（153个对照，141个病例，115个轻度认知障碍;年龄范围66 - 107; 63个女性; RUSH队列）。我们的首要目标是热休克蛋白家族A成员2（HSPA 2），它被确定为我们两个数据集中的关键驱动因素。在两种细胞系中验证了HSPA 2，其中过表达驱动APP突变细胞中淀粉样蛋白-40和淀粉样蛋白-42水平的进一步升高，以及修饰的神经胶质瘤系中微管相关蛋白tau和磷酸化tau的显著升高。这项工作进一步表明，研究基因和蛋白质表达的变化对于理解迟发性疾病至关重要，并进一步提名HSPA 2作为迟发性阿尔茨海默病过程的特定关键调节因子。
By integrating genome, transcriptome and proteome data, Petyuk et al. identify HSPA2 as a driver of pathology in Alzheimer’s disease, replicating the finding in an independent cohort and validating it in two in vitro systems. The results highlight the power of systems approaches for identifying genes involved in disease pathways. Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer’s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer’s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65–105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66–107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-β40 and amyloid-β42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer’s disease processes.
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影响因子：
4.8
作者：
Johnson, BD;Schumacher, RJ;Toft, DO
通讯作者：
Toft, DO
影响因子：
4.5
作者：
Ghazalpour A;Bennett B;Petyuk VA;Orozco L;Hagopian R;Mungrue IN;Farber CR;Sinsheimer J;Kang HM;Furlotte N;Park CC;Wen PZ;Brewer H;Weitz K;Camp DG 2nd;Pan C;Yordanova R;Neuhaus I;Tilford C;Siemers N;Gargalovic P;Eskin E;Kirchgessner T;Smith DJ;Smith RD;Lusis AJ
通讯作者：
Lusis AJ
影响因子：
7
作者：
Garge, Nikhil;Pan, Huaqin;Bunger, Maureen K.
通讯作者：
Bunger, Maureen K.
DOI：
10.1073/pnas.93.7.2719
发表时间：
1996-04-02
影响因子：
11.1
作者：
Hoshi, M;Takashima, A;Imahori, K
通讯作者：
Imahori, K
影响因子：
3.5
作者：
Corneveaux, Jason J.;Myers, Amanda J.;Huentelman, Matthew J.
通讯作者：
Huentelman, Matthew J.