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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.


Interactions between 42 topological modules.Red nodes: seed genes of modules > = 10; blue nodes: seed genes of modules < 10; green nodes: extensional modules. Node size corresponds to degree of module. The thickness of the edge is proportional to the weight, and the weight corresponds to strength of interactions.
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pone.0174964.g003: Interactions between 42 topological modules.Red nodes: seed genes of modules > = 10; blue nodes: seed genes of modules < 10; green nodes: extensional modules. Node size corresponds to degree of module. The thickness of the edge is proportional to the weight, and the weight corresponds to strength of interactions.

Mentions: To distinguish the core modules from those 42 significant modules, we constructed a network with nodes representing the modules and links representing shared PPI interactions between them (Fig 3). It showed that there are six modules (M37, M65, M80, M114, M155, and M197) with significantly higher degrees than that of the other modules (Table 2), which means that these six modules are the central modules underlying RE molecular pathologies[66].


Integrated network analysis reveals potentially novel molecular mechanisms and therapeutic targets of refractory epilepsies
Interactions between 42 topological modules.Red nodes: seed genes of modules > = 10; blue nodes: seed genes of modules < 10; green nodes: extensional modules. Node size corresponds to degree of module. The thickness of the edge is proportional to the weight, and the weight corresponds to strength of interactions.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0174964.g003: Interactions between 42 topological modules.Red nodes: seed genes of modules > = 10; blue nodes: seed genes of modules < 10; green nodes: extensional modules. Node size corresponds to degree of module. The thickness of the edge is proportional to the weight, and the weight corresponds to strength of interactions.
Mentions: To distinguish the core modules from those 42 significant modules, we constructed a network with nodes representing the modules and links representing shared PPI interactions between them (Fig 3). It showed that there are six modules (M37, M65, M80, M114, M155, and M197) with significantly higher degrees than that of the other modules (Table 2), which means that these six modules are the central modules underlying RE molecular pathologies[66].

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., &ldquo;presynaptic nicotinic acetylcholine receptors&rdquo;, &ldquo;signaling by insulin receptor&rdquo;). 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.