Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
BMC Bioinformatics. 2019 Dec 20;20(Suppl 24):680. doi: 10.1186/s12859-019-3249-8.
Emerging evidence suggests retroviruses play a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Specifically, activation of ancient viral genes embedded in the human genome is theorized to lead to motor neuron degeneration. We explore whether connections exist between ALS and retroviruses through protein interaction networks (PIN) and pathway analysis, and consider the potential roles in drug target discovery. Protein database and pathway/network analytical software including Ingenuity Pathway BioProfiler, STRING, and CytoScape were utilized to identify overlapping protein interaction networks and extract core cluster (s) of retroviruses and ALS.
Topological and statistical analysis of the ALS-PIN and retrovirus-PIN identified a shared, essential protein network and a core cluster with significant connections with both networks. The identified core cluster has three interleukin molecules IL10, Il-6 and IL-1B, a central apoptosis regulator TP53, and several major transcription regulators including MAPK1, ANXA5, SQSTM1, SREBF2, and FADD. Pathway enrichment analysis showed that this core cluster is associated with the glucocorticoid receptor singling and neuroinflammation signaling pathways. For confirmation purposes, we applied the same methodology to the West Nile and Polio virus, which demonstrated trivial connectivity with ALS, supporting the unique connection between ALS and retroviruses.
Bioinformatics analysis provides evidence to support pathological links between ALS and retroviral activation. The neuroinflammation and apoptotic regulation pathways are specifically implicated. The continuation and further analysis of large scale genome studies may prove useful in exploring genes important in retroviral activation and ALS, which may help discover new drug targets.
新出现的证据表明逆转录病毒在肌萎缩侧索硬化症（ALS）的病理生理学中起作用。具体来说，理论上嵌入人类基因组中的古老病毒基因的激活会导致运动神经元退化。我们通过蛋白质相互作用网络（PIN）和途径分析来探索 ALS 与逆转录病毒之间是否存在联系，并考虑在药物靶点发现中的潜在作用。利用蛋白质数据库和途径/网络分析软件，包括 Ingenuity Pathway BioProfiler、STRING 和 CytoScape，来识别重叠的蛋白质相互作用网络并提取逆转录病毒和 ALS 的核心簇。
ALS-PIN 和逆转录病毒-PIN 的拓扑和统计分析确定了一个共享的、基本的蛋白质网络和一个核心簇，与两个网络都有显著的连接。鉴定出的核心簇有三个白细胞介素分子 IL10、IL-6 和 IL-1B，一个中央凋亡调节因子 TP53，以及几个主要的转录调节因子，包括 MAPK1、ANXA5、SQSTM1、SREBF2 和 FADD。途径富集分析表明，该核心簇与糖皮质激素受体信号和神经炎症信号通路有关。为了验证目的，我们将相同的方法应用于西尼罗河病毒和脊髓灰质炎病毒，结果表明它们与 ALS 的连接微不足道，支持 ALS 与逆转录病毒之间的独特连接。
生物信息学分析提供了支持 ALS 与逆转录病毒激活之间病理联系的证据。神经炎症和凋亡调节途径特别涉及其中。对大规模基因组研究的进一步分析可能有助于探索在逆转录病毒激活和 ALS 中重要的基因，这可能有助于发现新的药物靶点。
