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

Epilepsy is estimated to affect 1-2% of the world population, yet remains poorly understood at a molecular level. We have previously established the roundworm Caenorhabditis elegans as a model for investigating genetic susceptibilities to seizure-like convulsions in vivo. Here we investigate the behavioral consequences of decreasing the activity of nematode gene homologs within the LIS1 pathway that are associated with a human cortical malformation termed lissencephaly. Bioinformatic analysis revealed the nud-2 gene, encoding the worm homolog of mammalian effectors of LIS1, termed NDE1 and NDEL1. Phenotypic analysis of animals targeted by RNA interference (RNAi) was performed using a pentylenetetrazole (PTZ) exposure paradigm to induce convulsions. Worms depleted for LIS1 pathway components (NUD-1, NUD-2, DHC-1, CDK-5, and CDKA-1) exhibited significant convulsions following PTZ and RNAi treatment. Strains harboring fluorescent markers for GABAergic neuronal architecture and synaptic vesicle trafficking were employed to discern putative mechanisms accounting for observed convulsion behaviors. We found that depletion of LIS1 pathway components resulted in defective GABA synaptic vesicle trafficking. We also utilized combinations of specific genetic backgrounds to create a sensitized state for convulsion susceptibility and discovered that convulsion effects were significantly enhanced when LIS-1 and other pathway components were compromised within the same animals. Thus, interactions among gene products with LIS-1 may mediate intrinsic thresholds of neuronal synchrony.
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PMID:Genetic interactions among cortical malformation genes that influence susceptibility to convulsions in C. elegans. 1699 38

Lissencephaly is a severe human neuronal migration defect characterized by a smooth cerebral surface, mental retardation and seizures. LIS1 was first gene cloned in an organism important for neuronal migration, as it was deleted or mutated in patients with lissencephaly in a heterozygous fashion. Studies in model organisms, particularly Aspergillus nidulans, as well as those in the mouse, have uncovered an evolutionarily conserved pathway that involves LIS1 and cytoplasmic dynein. This pathway codes for proteins in a complex with cytoplasmic dynein and positively regulates its conserved function in nuclear migration. This complex appears to be important for proliferation and neuronal survival as well as neuronal migration. One of the components of this complex, NDEL1, is a phosphoprotein that is a substrate for CDK5 (or CDK2 in fibroblasts) and Aurora-A, two mitotic kinases. CDK5-phosphorylated NDEL1 binds to 14-3-3epsilon, which protects it from phosphatase attack. Interestingly, 14-3-3epsilon is located 1 Mb from LIS1 and is heterozygously deleted with LIS1 in patients with a severe form of lissencephaly, Miller-Dieker syndrome. Mouse models confirm that 14-3-3epsilon plays an important role in neuronal migration, and mice that are double heterozygotes for mutations in Lis1 and 14-3-3epsilon, display more severe neuronal migration defects. The identification of LIS1 as the first lissencephaly gene, and the first gene required for neuronal migration has revealed the importance of the regulation of cytoplasmic dynein in the control of neuronal migration by modulating nuclear migration in a pathway conserved in virtually all eukaryotes.
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PMID:Lissencephaly and LIS1: insights into the molecular mechanisms of neuronal migration and development. 1785 Jun 24

Heterozygous LIS1 mutations are the most common cause of human lissencephaly, a human neuronal migration defect, and DCX mutations are the most common cause of X-linked lissencephaly. Lissencephaly is characterized by a smooth cerebral surface, thick cortex and dilated lateral ventricles associated with mental retardation and seizures due to defective neuronal migration. Lissencephaly due to the heterozygous loss of the gene LIS1 is a good example of a haploinsufficiency disorder. LIS1 was deleted or mutated in a large proportion of patients with lissencephaly in a heterozygous fashion. A series of studies discovered that LIS1 is an essential regulator of cytoplasmic dynein. Notably, the role of LIS1 in regulating dynein activity is highly conserved among eukaryotes. In particular, we reported that LIS1 and NDEL1 are essential for dynein transport to the plus-end of microtubules by kinesin, which is essential to maintain the proper distribution of cytoplasmic dynein within the cell. In addition, we report that mNUDC (mammalian NUDC) interacts with kinesin-1 and is required for the anterograde transport of a cytoplasmic dynein complex by kinesin-1. A microtubule organization and motor proteins are further modulated by post-translational modifications, including phosphorylation and palmitoylation. These modifications share a common pathway with mitotic cell division. For example, Aurora-A is activated during neurite elongation, and phosphorylates NDEL1, which facilitates microtubule extension into neurite processes. Elucidations of molecular pathways involving neuronal migrations provide us a chance to design a novel strategy for neurological disorder due to defective neuronal migration. For example, inhibition of calpain protects LIS1 from proteolysis resulting in the augmentation of LIS1 levels, which leads to rescue of the phenotypes that are observed in Lis1+/- mice. Endeavoring to address the regulation of the microtubule network and motor proteins will help in understanding not only corticogenesis but neurodegenerative disorders.
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PMID:A unique role of dynein and nud family proteins in corticogenesis. 2239 75

Nuclear distribution element-like 1 (NDEL1/NUDEL) is a mammalian homolog of the Aspergillus nidulans nuclear distribution molecule NudE. NDEL1 plays a critical role in neuronal migration, neurite outgrowth and neuronal positioning during brain development; however within the adult central nervous system, limited information is available regarding NDEL1 expression and functions. Here, the goal was to examine inducible NDEL1 expression in the adult mouse forebrain. Immunolabeling revealed NDEL1 within the forebrain, including the cortex and hippocampus, as well as the midbrain and hypothalamus. Expression was principally localized to perikarya. Using a combination of immunolabeling and RNA seq profiling, we detected a marked and long-lasting upregulation of NDEL1 expression within the hippocampus following a pilocarpine-evoked repetitive seizure paradigm. Chromatin immunoprecipitation (ChIP) analysis identified a cAMP response element-binding protein (CREB) binding site within the CpG island proximal to the NDEL1 gene, and in vivo transgenic repression of CREB led to a marked downregulation of seizure-evoked NDEL1 expression. Together these data indicate that NDEL1 is inducibly expressed in the adult nervous system, and that signaling via the CREB/CRE transcriptional pathway is likely involved. The role of NDEL1 in neuronal migration and neurite outgrowth during development raises the interesting prospect that inducible NDEL1 in the mature nervous system could contribute to the well-characterized structural and functional plasticity resulting from repetitive seizure activity.
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PMID:Status epilepticus stimulates NDEL1 expression via the CREB/CRE pathway in the adult mouse brain. 2729 8