Protein network analysis to prioritize key genes in amyotrophic lateral sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease, progressive nature characterizes by loss of both upper and lower motor neuron functions. One of the major challenge is to understand the mechanism of ALS multifactorial nature. We aimed to explore some key genes related to ALS through bioinformatics methods for its therapeutic intervention. Here, we applied a systems biology approach involving experimentally validated 148 ALS-associated proteins and construct ALS protein-protein interaction network (ALS-PPIN). The network was further statistically analysed and identified bottleneck-hubs. The network is also subjected to identify modules which could have similar functions. The interaction between the modules and bottleneck-hubs provides the functional regulatory role of the ALS mechanism. The ALS-PPIN demonstrated a hierarchical scale-free nature. We identified 17 bottleneck-hubs, in which <i>CDC5L</i>, <i>SNW1, TP53, SOD1,</i> and <i>VCP</i> were the high degree nodes (hubs) in ALS-PPIN. <i>CDC5L</i> was found to control highly cluster modules and play a vital role in the stability of the overall network followed by <i>SNW1</i>, <i>TP53, SOD1,</i> and <i>VCP</i>. <i>HSPA5 and HSPA8 acting</i> as a common connector for <i>CDC5L</i> and <i>TP53</i> bottleneck-hubs. The functional and disease association analysis showed ALS has a strong correlation with mRNA processing, protein deubiquitination, and neoplasms, nervous system, immune system disease classes. In the future, biochemical investigation of the observed bottleneck-hubs and their interacting partners could provide a further understanding of their role in the pathophysiology of ALS.