Association between ALS and retroviruses: evidence from bioinformatics analysis

Jon P Klein,Zhifu Sun,Nathan P Staff

doi:10.1186/s12859-019-3249-8

Abstract

BackgroundEmerging 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.ResultsTopological 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.ConclusionsBioinformatics 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.

Highlights

Emerging evidence suggests retroviruses play a role in the pathophysiology of amyotrophic lateral sclerosis (ALS)
ALS autopsy studies have revealed that human endogenous retrovirus K (HERV-K) expression is significantly elevated in brain tissues of ALS patients [15]
The computerized process involves the following steps: 1) Retrieve associated proteins from IPA; 2) Obtain protein connection scores in STRING; 3) Import protein connection score files and construct protein interaction networks in CytoScape 3.6; 4) Conduct network topological and statistical analysis using multiple CytoScape 3.6 Plug-in tools; and 5) Identify existing overlapping protein core cluster (s) that are shared by both networks, 6) perform functional pathway analysis

Summary

Introduction

Emerging evidence suggests retroviruses play a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Activation of ancient viral genes embedded in the human genome is theorized to lead to motor neuron degeneration. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons of the brain and spinal cord. ALS autopsy studies have revealed that human endogenous retrovirus K (HERV-K) expression is significantly elevated in brain tissues of ALS patients [15]. Activation of HERV-K genes is noted to kill healthy human neurons grown in cell cultures [16]. Human endogenous retrovirus (HERV) within intergenic regions comprises ~8% of human genome but remains dormant by means of evolutionary selection and is not expressed in healthy persons [17]. Endogenous retroviral sequences can become active and expressed [18]

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