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      Integrated network analysis reveals potentially novel molecular mechanisms and therapeutic targets of refractory epilepsies

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          Abstract

          Epilepsy is a complex neurological disorder and a significant health problem. The pathogenesis of epilepsy remains obscure in a significant number of patients and the current treatment options are not adequate in about a third of individuals which were known as refractory epilepsies (RE). Network medicine provides an effective approach for studying the molecular mechanisms underlying complex diseases. Here we integrated 1876 disease-gene associations of RE and located those genes to human protein-protein interaction (PPI) network to obtain 42 significant RE-associated disease modules. The functional analysis of these disease modules showed novel molecular pathological mechanisms of RE, such as the novel enriched pathways (e.g., “presynaptic nicotinic acetylcholine receptors”, “signaling by insulin receptor”). Further analysis on the relationships between current drug targets and the RE-related disease genes showed the rational mechanisms of most antiepileptic drugs. In addition, we detected ten potential novel drug targets (e.g., KCNA1, KCNA4-6, KCNC3, KCND2, KCNMA1, CAMK2G, CACNB4 and GRM1) located in three RE related disease modules, which might provide novel insights into the new drug discovery for RE therapy.

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          Most cited references60

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          Gene Ontology: tool for the unification of biology

          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            FatiGO: a web tool for finding significant associations of Gene Ontology terms with groups of genes.

            We present a simple but powerful procedure to extract Gene Ontology (GO) terms that are significantly over- or under-represented in sets of genes within the context of a genome-scale experiment (DNA microarray, proteomics, etc.). Said procedure has been implemented as a web application, FatiGO, allowing for easy and interactive querying. FatiGO, which takes the multiple-testing nature of statistical contrast into account, currently includes GO associations for diverse organisms (human, mouse, fly, worm and yeast) and the TrEMBL/Swissprot GOAnnotations@EBI correspondences from the European Bioinformatics Institute.
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              Epilepsy: new advances.

              Epilepsy affects 65 million people worldwide and entails a major burden in seizure-related disability, mortality, comorbidities, stigma, and costs. In the past decade, important advances have been made in the understanding of the pathophysiological mechanisms of the disease and factors affecting its prognosis. These advances have translated into new conceptual and operational definitions of epilepsy in addition to revised criteria and terminology for its diagnosis and classification. Although the number of available antiepileptic drugs has increased substantially during the past 20 years, about a third of patients remain resistant to medical treatment. Despite improved effectiveness of surgical procedures, with more than half of operated patients achieving long-term freedom from seizures, epilepsy surgery is still done in a small subset of drug-resistant patients. The lives of most people with epilepsy continue to be adversely affected by gaps in knowledge, diagnosis, treatment, advocacy, education, legislation, and research. Concerted actions to address these challenges are urgently needed.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                7 April 2017
                2017
                : 12
                : 4
                : e0174964
                Affiliations
                [1 ]Department of Biomedical Engineering, Faculty of Electronic Information and Electrical Engineering, Dalian University of Technology, Dalian, China
                [2 ]Liaoning Provincial Key Laboratory of Cerebral Diseases, Institute for Brain Disorders, Dalian Medical University, Dalian, China
                [3 ]Shanghai Medical College, Fudan University, Shanghai, China
                [4 ]College of Electronics and Information Engineering, Tongji University, Shanghai, China
                [5 ]School of Computer and Information Technology and Beijing Key Lab of Traffic Data Analysis and Mining, Beijing Jiaotong University, Beijing, China
                [6 ]Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
                [7 ]Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Lab. for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, China
                [8 ]Research Center for the Control Engineering of Translational Precision Medicine, Dalian University of Technology, Dalian, China
                [9 ]State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian, China
                University of Catanzaro, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: CS XZ.

                • Data curation: HC PS GL YW PZ YZ.

                • Formal analysis: XZ CS WJ HC PS JY.

                • Funding acquisition: CS XZ.

                • Investigation: CS XZ.

                • Methodology: CS XZ.

                • Project administration: CS XZ.

                • Resources: XZ CS.

                • Software: XZ CS HC.

                • Supervision: CS XZ.

                • Validation: CS XZ HC PS XY TZ.

                • Visualization: XZ CS HC.

                • Writing – original draft: XZ CS HC WJ PS JY.

                • Writing – review & editing: XZ CS HC WJ PS JY.

                Article
                PONE-D-16-37393
                10.1371/journal.pone.0174964
                5384674
                28388656
                45b8ecfe-5ca9-4f09-bd4c-224e964402f7
                © 2017 Chu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 September 2016
                : 19 March 2017
                Page count
                Figures: 6, Tables: 5, Pages: 22
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 61105055
                Award Recipient :
                Funded by: National Natural Science Foundation of China (CN)
                Award ID: 81230086
                Award Recipient :
                Funded by: National science and technology major projects subject
                Award ID: 2012ZX09503-001-003
                Award Recipient :
                Funded by: Hui-Chun Chin and Tsung-Dao Lee Chinese Undergraduate Research Endowment (CURE)
                Award ID: 14032
                Award Recipient :
                The study is supported by National Science and Technology Major Projects Subject (No. 2012ZX09503-001-003) to Changkai Sun ( http://www.most.gov.cn/), National Natural Science Foundation of China (Nos. 61105055, 81230086) to Xuezhong Zhou ( https://isisn.nsfc.gov.cn/), Special program of Traditional Chinese medicine (No. 201407001) to Xuezhong Zhou, and Hui-Chun Chin and Tsung-Dao Lee Chinese Undergraduate Research Endowment (No.14032) to Pin Sun. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Neurology
                Epilepsy
                Medicine and Health Sciences
                Pharmacology
                Drug Research and Development
                Drug Discovery
                Biology and Life Sciences
                Genetics
                Gene Identification and Analysis
                Genetic Networks
                Computer and Information Sciences
                Network Analysis
                Genetic Networks
                Computer and Information Sciences
                Network Analysis
                Protein Interaction Networks
                Biology and Life Sciences
                Biochemistry
                Proteomics
                Protein Interaction Networks
                Medicine and Health Sciences
                Pharmacology
                Drug Research and Development
                Drug Marketing
                Biology and Life Sciences
                Biochemistry
                Neurochemistry
                Neurotransmitters
                Glutamate
                Biology and Life Sciences
                Neuroscience
                Neurochemistry
                Neurotransmitters
                Glutamate
                Biology and Life Sciences
                Biochemistry
                Proteins
                Transmembrane Receptors
                Acetylcholine Receptors
                Nicotinic Acetylcholine Receptors
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Transmembrane Receptors
                Acetylcholine Receptors
                Nicotinic Acetylcholine Receptors
                Biology and Life Sciences
                Biophysics
                Ion Channels
                Ion Channel Gating
                Physical Sciences
                Physics
                Biophysics
                Ion Channels
                Ion Channel Gating
                Biology and Life Sciences
                Physiology
                Electrophysiology
                Ion Channels
                Ion Channel Gating
                Medicine and Health Sciences
                Physiology
                Electrophysiology
                Ion Channels
                Ion Channel Gating
                Biology and Life Sciences
                Physiology
                Electrophysiology
                Neurophysiology
                Ion Channels
                Ion Channel Gating
                Medicine and Health Sciences
                Physiology
                Electrophysiology
                Neurophysiology
                Ion Channels
                Ion Channel Gating
                Biology and Life Sciences
                Neuroscience
                Neurophysiology
                Ion Channels
                Ion Channel Gating
                Biology and Life Sciences
                Biochemistry
                Proteins
                Ion Channels
                Ion Channel Gating
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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