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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.


Related in: MedlinePlus

Heat map of 94 common pathways corresponding to enrichment in 20 modules.X-axis: pathway; Y-axis: module. Color key from blue to red is representative of low to high enrichment (p value from large to small). If the cross of module and pathway form a black cell, it refers to that the pathway in the module is not enriched.
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pone.0174964.g004: Heat map of 94 common pathways corresponding to enrichment in 20 modules.X-axis: pathway; Y-axis: module. Color key from blue to red is representative of low to high enrichment (p value from large to small). If the cross of module and pathway form a black cell, it refers to that the pathway in the module is not enriched.

Mentions: Most modules (except module M139 and M150) have their enriched pathways using six pathway databases in KOBAS 2.0. However, we only obtained 317 enriched pathways (corrected p-value<0.05) for 28 modules using the Reactome database. The 317 pathways were classified into two types according to whether it was located in a single module or multiple modules. We call the former as “individual pathway” and the latter as “common pathway” for RE. Statistical analysis yielded 223 individual pathways located on 27 modules, and 94 common pathways distributed across 20 modules. We generated a heat map to display the 94 common pathways corresponding to their enrichments in 20 modules (Fig 4). It showed that the common enriched pathways also referred to the branch of transmission across chemical synapses, neurotransmitter receptor binding and downstream transmission in the postsynaptic cell. Neurotransmitter secretion is triggered by the influx of Ca2+ through voltage-gated channels, which gives rise to a transient increase in Ca2+ concentration within the presynaptic terminal. Module M37, M65 and M155 had significant enrichment pathways (red color) among the 20 modules. For module M37, the highly enriched individual pathway was “Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins”. Module M65 was closely related to the “Activation of NMDA receptor upon glutamate binding and postsynaptic events” “Glutamate Binding, Activation of AMPA Receptors and Synaptic Plasticity” “Trafficking of AMPA receptors” and “Unblocking of NMDA receptor, glutamate binding and activation”. Module M155 was most related to the “activation of voltage-gated potassium channels”, “GABA receptor activation”. NMDA receptor-mediated signal transduction is critical for synaptic plasticity. In acute and chronic seizures, a selective NMDA receptor antagonist has broad clinical application prospects[5]. It has been shown that CaV3.2 channels regulate NMDA receptor mediated transmission and subsequent NMDA receptor dependent plasticity of AMPA-R-mediated transmission[67].


Integrated network analysis reveals potentially novel molecular mechanisms and therapeutic targets of refractory epilepsies
Heat map of 94 common pathways corresponding to enrichment in 20 modules.X-axis: pathway; Y-axis: module. Color key from blue to red is representative of low to high enrichment (p value from large to small). If the cross of module and pathway form a black cell, it refers to that the pathway in the module is not enriched.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0174964.g004: Heat map of 94 common pathways corresponding to enrichment in 20 modules.X-axis: pathway; Y-axis: module. Color key from blue to red is representative of low to high enrichment (p value from large to small). If the cross of module and pathway form a black cell, it refers to that the pathway in the module is not enriched.
Mentions: Most modules (except module M139 and M150) have their enriched pathways using six pathway databases in KOBAS 2.0. However, we only obtained 317 enriched pathways (corrected p-value<0.05) for 28 modules using the Reactome database. The 317 pathways were classified into two types according to whether it was located in a single module or multiple modules. We call the former as “individual pathway” and the latter as “common pathway” for RE. Statistical analysis yielded 223 individual pathways located on 27 modules, and 94 common pathways distributed across 20 modules. We generated a heat map to display the 94 common pathways corresponding to their enrichments in 20 modules (Fig 4). It showed that the common enriched pathways also referred to the branch of transmission across chemical synapses, neurotransmitter receptor binding and downstream transmission in the postsynaptic cell. Neurotransmitter secretion is triggered by the influx of Ca2+ through voltage-gated channels, which gives rise to a transient increase in Ca2+ concentration within the presynaptic terminal. Module M37, M65 and M155 had significant enrichment pathways (red color) among the 20 modules. For module M37, the highly enriched individual pathway was “Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins”. Module M65 was closely related to the “Activation of NMDA receptor upon glutamate binding and postsynaptic events” “Glutamate Binding, Activation of AMPA Receptors and Synaptic Plasticity” “Trafficking of AMPA receptors” and “Unblocking of NMDA receptor, glutamate binding and activation”. Module M155 was most related to the “activation of voltage-gated potassium channels”, “GABA receptor activation”. NMDA receptor-mediated signal transduction is critical for synaptic plasticity. In acute and chronic seizures, a selective NMDA receptor antagonist has broad clinical application prospects[5]. It has been shown that CaV3.2 channels regulate NMDA receptor mediated transmission and subsequent NMDA receptor dependent plasticity of AMPA-R-mediated transmission[67].

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.


Related in: MedlinePlus