Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Photosensitive seizures occur most commonly in childhood and adolescence, usually as a manifestation of complex idiopathic generalized epilepsies (IGEs). Molecular mechanisms underlying this condition are yet to be determined because no susceptibility genes have been identified. The NEDD4-2 (Neuronally Expressed Developmentally Downregulated 4) gene encodes a ubiquitin protein ligase proposed to regulate cell surface levels of several ion channels, receptors and transporters involved in regulating neuronal excitability, including voltage-gated sodium channels (VGSCs), the most clinically relevant of the epilepsy genes. The regulation of NEDD4-2 in vivo involves complex interactions with accessory proteins in a cell type specific manner. We screened NEDD4-2 for mutations in a cohort of 253 families with IGEs. We identified three NEDD4-2 missense changes in highly conserved residues; S233L, E271A and H515P in families with photosensitive generalized epilepsy. The NEDD4-2 variants were as effective as wild-type NEDD4-2 in downregulating the VGSC subtype Na(v)1.2 when assessed in the Xenopus oocyte heterologous expression system showing that the direct interaction with the ion channel was not altered by these variants. These data raise the possibility that photosensitive epilepsy may arise from defective interaction of NEDD4-2 with as yet unidentified accessory or target proteins.
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PMID:NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity. 1733 Nov 6

In the brain, murine double minute-2 (Mdm2), an E3-ubiquitin ligase, modulates neuronal excitability by regulating glutamate receptor and postsynaptic density 95 (PSD95) levels through ubiquitination. Thus, Mdm2 is relevant to epileptic seizures in human patients. Although phosphorylation at serine (S) 166 site by AKT increases Mdm2 activity, phosphatases of Mdm2 have been still elusive. Here, we demonstrate the novel function of pyridoxal-5'-phosphate phosphatase/chronophin (PLPP/CIN) in Mdm2 dephosphorylation that may negatively regulate PSD95 ubiquitination. As compared to wild-type mice, PLPP/CIN knockout (PLPP/CIN-/-) mice showed the brief seizure activity and the higher Mdm2-S166 phosphorylation following kainic acid (KA) injection, independent of AKT activity. In addition, PLPP/CIN-/- mice demonstrated the increases in Mdm2-PSD95 binding and PSD95 ubiquitination, accompanied by the decreases in Mdm2 ubiquitination and PSD95-NR2A (a subunit of N-methyl-d-aspartate receptor) bindings. Human PLPP/CIN over-expressing transgenic (PLPP/CINTg) mice reversed these phenomena. In addition, Mdm2 knockdown abolished PSD95 ubiquitination and increased KA-induced seizure activity in PLPP/CIN-/- mice without affecting AKT activity and protein levels of p53 and neural precursor cell expressed developmentally down-regulated gene 4-like (NEDD4-2). Therefore, we suggest that PLPP/CIN may be a potential therapeutic target for epilepsy and Mdm2-associated neurological diseases.
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PMID:PLPP/CIN-mediated Mdm2 dephosphorylation increases seizure susceptibility via abrogating PSD95 ubiquitination. 3256 13