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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Disease module network.(A) Protein classification network of module M155. The protein nodes are color-coded. Light pink nodes: currently known epilepsy drug targets which are not seed genes; green nodes: currently known drug targets, not specific for epilepsy, which are not seed genes; red nodes: currently unknown drug targets which are also not seed genes; blue nodes: currently known epilepsy drug targets which are also seed genes; yellow nodes: currently known drug targets—seed genes, not specific for epilepsy; purple nodes: currently unknown drug targets—seed genes, not specific for epilepsy. (B) Protein classification network of module M65. The node coloring is the same as that of module M155.
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pone.0174964.g006: Disease module network.(A) Protein classification network of module M155. The protein nodes are color-coded. Light pink nodes: currently known epilepsy drug targets which are not seed genes; green nodes: currently known drug targets, not specific for epilepsy, which are not seed genes; red nodes: currently unknown drug targets which are also not seed genes; blue nodes: currently known epilepsy drug targets which are also seed genes; yellow nodes: currently known drug targets—seed genes, not specific for epilepsy; purple nodes: currently unknown drug targets—seed genes, not specific for epilepsy. (B) Protein classification network of module M65. The node coloring is the same as that of module M155.

Mentions: A disease module, a local neighborhood of the interactome whose perturbation is associated with epilepsy, can be mechanistically linked to a particular disease phenotype[70,72]. The precise identification of such disease modules could help with the elucidation of molecular mechanisms, identification of new disease genes, and related signaling pathways, and aid with rational drug target identification[69]. Although module M37 had the greatest number of seed genes, there were no available AEDs for module M37, which had only 10 (10/305 = 3.3%) proteins targeted by drugs for the treatment of non-epileptic disorders. Module M155 had the most seed genes and the greatest number of drugs when RR> = 2.0. From the aforementioned functional analysis, Module M155 can be identified as one of the most important modules for drug discovery. The most enriched terms are ion transport for BP, ion channel complex for CC, gated channel activity for MF, and the enriched pathway is the activation of voltage gated potassium channels, which is the only pathway under voltage gated potassium channels in the Reactome database. Potassium channels are important determinants of seizure susceptibility by modulating the electrical activity of neuronal and non-neuronal cells in the brain. The 141 proteins of module M155 were classified into six types on the basis of whether seed gene or drug target (Fig 6A) and there were 43(43/141 = 30.5%) proteins located in the pathway of activation of voltage-gated potassium channels.


Integrated network analysis reveals potentially novel molecular mechanisms and therapeutic targets of refractory epilepsies
Disease module network.(A) Protein classification network of module M155. The protein nodes are color-coded. Light pink nodes: currently known epilepsy drug targets which are not seed genes; green nodes: currently known drug targets, not specific for epilepsy, which are not seed genes; red nodes: currently unknown drug targets which are also not seed genes; blue nodes: currently known epilepsy drug targets which are also seed genes; yellow nodes: currently known drug targets—seed genes, not specific for epilepsy; purple nodes: currently unknown drug targets—seed genes, not specific for epilepsy. (B) Protein classification network of module M65. The node coloring is the same as that of module M155.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384674&req=5

pone.0174964.g006: Disease module network.(A) Protein classification network of module M155. The protein nodes are color-coded. Light pink nodes: currently known epilepsy drug targets which are not seed genes; green nodes: currently known drug targets, not specific for epilepsy, which are not seed genes; red nodes: currently unknown drug targets which are also not seed genes; blue nodes: currently known epilepsy drug targets which are also seed genes; yellow nodes: currently known drug targets—seed genes, not specific for epilepsy; purple nodes: currently unknown drug targets—seed genes, not specific for epilepsy. (B) Protein classification network of module M65. The node coloring is the same as that of module M155.
Mentions: A disease module, a local neighborhood of the interactome whose perturbation is associated with epilepsy, can be mechanistically linked to a particular disease phenotype[70,72]. The precise identification of such disease modules could help with the elucidation of molecular mechanisms, identification of new disease genes, and related signaling pathways, and aid with rational drug target identification[69]. Although module M37 had the greatest number of seed genes, there were no available AEDs for module M37, which had only 10 (10/305 = 3.3%) proteins targeted by drugs for the treatment of non-epileptic disorders. Module M155 had the most seed genes and the greatest number of drugs when RR> = 2.0. From the aforementioned functional analysis, Module M155 can be identified as one of the most important modules for drug discovery. The most enriched terms are ion transport for BP, ion channel complex for CC, gated channel activity for MF, and the enriched pathway is the activation of voltage gated potassium channels, which is the only pathway under voltage gated potassium channels in the Reactome database. Potassium channels are important determinants of seizure susceptibility by modulating the electrical activity of neuronal and non-neuronal cells in the brain. The 141 proteins of module M155 were classified into six types on the basis of whether seed gene or drug target (Fig 6A) and there were 43(43/141 = 30.5%) proteins located in the pathway of activation of voltage-gated potassium channels.

View Article: PubMed Central - PubMed

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.

No MeSH data available.