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)

This study has examined cellular and molecular aspects of glial cell function in a newly described long-lived myelin deficient rat mutant. In contrast to the shorter-lived mutants which died at 25-30 days, the longer-lived mutant rats lived to 75-80 days of age. Despite living longer, these mutants had a similar frequency of seizures to their younger counterparts. In the spinal cord and optic nerves of the older mutants, myelinated fibres in similar numbers to those seen in the younger myelin deficient rats were present. However, the total glial cell numbers were markedly reduced with few remaining normal appearing oligodendrocytes, and very few microglia compared to the younger mutants. In addition, little or no cell death or division was seen in the longer-lived rats. However, there was some evidence of ongoing myelination and the persistence of immature oligodendrocytes or their progenitors in the older mutant. There was some continued myelin gene expression, although this was at much reduced levels compared to normal, with proteolipid protein and myelin basic protein being most affected. In situ hybridization analysis for proteolipid protein mRNA showed that few proteolipid protein expressing oligodendrocytes remained in the 70-80-day-old mutant. Polymerase chain reaction analysis of exon 3 of the long-lived mutant revealed the same point mutation as described in the younger myelin deficient rat.
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PMID:Oligodendrocyte survival and function in the long-lived strain of the myelin deficient rat. 858 95

This study describes a new sex-linked myelin mutation in the mouse, jimpy 4J (Plpjp-4J), located in or very close to the proteolipid protein (Plp) gene. The Plpjp-4J/Y phenotype includes tremor, seizures, death during the 4th postnatal week, and the most severe central nervous system hypomyelination yet described in any mouse carrying a single myelin mutation. The few myelin sheaths are present in early myelinating areas where they form clusters of thin, usually loosely wrapped membranes which show several variations of morphology at their extracellular leaflets. Numbers of mature oligodendrocytes are sharply reduced; pycnotic glial nuclei and foamy cells are numerous. Astrocytosis is a prominent feature. No PLP protein is detected by immunoblotting in Plpjp-4J/Y brain but in spinal cord a faint band is present. Myelin basic protein and characteristic myelin lipids are also sharply reduced in both brain and spinal cord. Despite the qualitative similarity of the phenotypes reported in these and previous studies, DNA analysis demonstrate that Plpjp-4J is not a recurrence of the well known Plp mouse mutations jimpy (Plpjp) or myelin synthesis deficiency (Plpjp-msd).
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PMID:Jimpy 4J: a new X-linked mouse mutation producing severe CNS hypomyelination. 882 19

Spontaneous mutations that perturb myelination occur in a range of species including man, and together with engineered mutations have been used to study disease, normal myelination and axon/glial inter-relationships. Only a minority of the currently defined mutations have an apparently simple pathogenesis due to lack of a functional protein. Mutations in the myelin basic protein gene lead to a lack of protein, resulting in changes in the structure of myelin, which can be rescued by transgenic complementation. The pathogenesis of autosomal dominant and X-linked mutations affecting either oligodendrocytes or Schwann cells is more complex. Point mutations may act in a dominant negative manner and gene dosage is clearly linked to phenotypic change. Mutations in regulatory genes, such as those encoding transcription factors, can also disturb myelination by selected cell types. Other less-well studied and unexpected consequences of myelin mutations, such as seizures in mutations affecting genes expressed in Schwann cells and axonal changes associated with dysmyelination, are also considered. With the major developments in gene mapping and cloning it is now relevant to study mutations in a variety of species with the real prospect of defining their molecular basis. Examples are given of unusual, but potentially useful, uncharacterized mutations in dog and bovine.
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PMID:Myelin mutants: model systems for the study of normal and abnormal myelination. 888 16

The shaking pup, a canine mutant, carries a point mutation in the myelin proteolipid protein (PLP) gene that causes dysmyelination of the central nervous system (CNS) with resultant tremor, seizures, and other persistent neurological deficits. The developmental potential of glial cells in the shaking pup CNS and peripheral nervous system (PNS) was evaluated by quantitative analysis of the expression of several glial-specific genes. All of the myelin-associated genes demonstrated developmental patterns of expression similar to those observed in the controls, but at significantly reduced levels. Expression of the genes for the major CNS myelin proteins, PLP and the myelin basic protein, are most dramatically affected in the shaking pup, although reduced expression levels are observed for other oligodendrocyte-specific genes such as 2',3'-cyclic nucleotide 3'phosphodiesterase and glucose phosphate dehydrogenase. The pattern of gene expression in the shaking pup indicates that the oligodendrocytes experience an inhibition in development after the myelination program has begun. There appears to be little evidence for an astrocytic response to the dysmyelinating condition at the RNA level, but we present evidence for ectopic expression of P0 mRNA in the CNS. Expression of the P0 and PLP genes in the sciatic nerve appears to be normal, reinforcing previous reports that PNS myelination is unaffected by the mutation in the PLP gene.
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PMID:Molecular analysis of glial cell development in the canine 'shaking pup' mutant. 889 46

We detected the level of myelin basic protein (MBP) in the serum of experimental epilepsy rats using simplified MBP ELISA, and the myelin sheaths of their brain with MBP immuno-histochemistry (IHC) and transmitted electronmicroscopy (TEM) in order to explore the relation of brain myelin sheaths and MBP to the pathogenic mechanism of epileptic seizure. The results show that the serum MBP level in the experimental epilepsy group is significantly higher than that in the control groups (P < 0.05), and is similar to that in some patients with generalized myoclonic seizures reported by us previously. The IHC and TEM findings in the brain of epilepsy rats indicate that the lamelliform structure of myelin sheaths in some part of hippocampus region becomes relaxing, disorderly and homogenized. Our studies imply that epileptic seizures are associated with MBP release from the subtle damaged regions of myelin sheaths during epileptic seizures, and the change of MBP component in myelin sheath may play and important role in the pathogenesis of epilepsy.
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PMID:[The serum MBP, myelin sheath immunohistochemistry and electromicroscope of expetrimental epilepsy rats]. 938 52

Shiverer (shi) mice, which are neurologically mutant, lack a large portion of the gene for the myelin basic proteins (MBPs), have virtually no myelin in their central nervous system (CNS), and shiver, undergo seizures, and die early. At least five types of MBPs (21.5, 18.5, 17.3, 17.2 and 14.0 kDa) are known to be generated through alternative splicing from a single MBP gene. We have produced transgenic shi mice carrying a cDNA encoding mouse 14-kDa MBP isoform, the most abundant form of MBPs, under control of a mouse MBP gene promoter, and showed that expression of the 14-kDa MBP can restore CNS myelination. To test whether the 17.2-kDa MBP isoform, one of the minor components of MBPs, can also elicit myelination in homozygous shi mutants, we produced seven independent transgenic shi mice carrying cDNA encoding the mouse 17.2-kDa MBP isoform, and the transcription of which was driven by a mouse MBP gene promoter. The axons in the cerebellum of one transgenic line, which exhibited the highest expression of transgene-derived mRNA ( approximately 50% of the level of total MBP mRNA in the normal mouse brain), were myelinated. This mouse exhibited nearly normal behavior. These findings indicate that the 17.2-kDa MBP isoform, even when the only 17.2-kDa MBP isoform is present, has the ability to elicit CNS myelination in transgenic shi mice. This transgenic strategy will be useful for elucidating the role of each type of MBP isoform in CNS myelinogenesis.
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PMID:Overexpression of a minor component of myelin basic protein isoform (17.2 kDa) can restore myelinogenesis in transgenic shiverer mice. 951 36

c-myc is a member of the helix-loop-helix/leucine zipper family of proteins that modulate the transcriptional activity of specific target genes. Although aberrant c-myc expression has been reported to play a role in multistage carcinogenesis in astrocytic gliomas, little is known about the effects of the expression of c-myc on oligodendrocytes. Using transgenic animals expressing a human c-myc oncogene under transcriptional control of the myelin basic protein gene, we investigated the effect of overexpression of this oncogene in oligodendrocytes. The MBP/c-myc transgenic mice developed severe neurological disturbances characterized by action tremors and recurrent seizures, and premature death during postnatal weeks three to five. Affected transgenic mice of various strains had severely hypomyelinated central nervous systems and expressed low levels of c-myc, myelin basic protein (MBP) and proteolipid protein (PLP) mRNAs in the brain. These c-myc transgenic mice also exhibited an increased number of TUNEL positive nuclei, which in most cases were located in cells that expressed c-myc, as judged by double immunohistochemistry. There was no evidence of brain tumors in the c-myc transgenic mice, including heterozygous mice from two strains that had normal lifespans. These observations indicate that the myelin deficiency observed in the MBP/c-myc transgenic animals results from a cytotoxic effect of the c-myc transgene.
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PMID:Failure of central nervous system myelination in MBP/c-myc transgenic mice: evidence for c-myc cytotoxicity. 957 93

The basic helix-loop-helix transcription factor c-Myc is a potent trigger of programmed cell death when overexpressed during late oligodendrocyte development in transgenic mice. Here we provide evidence that c-Myc can act synergistically with the Pit, Oct, Unc homeodomain transcription factor Oct-6 to produce myelin disease pathogenesis in transgenic mice. More than 70% of c-myc/Oct-6 bitransgenic mice, obtained from crosses between phenotypically normal heterozygous mice of various My (c-Myc) and Oc (Oct-6) transgenic strains that express c-myc and oct-6 transgenes under transcriptional control of the myelin basic protein gene, developed severe neurological disturbances characterized by action tremors, recurrent seizures, and premature death. Affected bitransgenic mice exhibited multiple hypomyelinated lesions in the white matter that did not stain with myelin-specific antibodies against myelin basic protein, proteolipid protein, CNPase, and myelin-associated glycoprotein. The mice also exhibited a larger number of terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling positive cells in the white matter as well as ultrastructural evidence of glial cell death and astrogliosis. These observations indicate that the myelin lesions observed in the c-myc/oct-6 bitransgenic mice result from the untimely programmed cell death of oligodendroglia and that the c-myc and oct-6 transgenes act synergistically in producing the lesions.
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PMID:Oligodendrocyte programmed cell death and central myelination deficiency induced in transgenic mice by synergism between c-Myc and Oct-6. 1051 74

Oligodendrocytes are glial cells devoted to the production of myelin sheaths. Myelination of the CNS occurs essentially after birth. To delineate both the times of oligodendrocyte proliferation and myelination, as well as to study the consequence of dysmyelination in vivo, a model of inducible dysmyelination was developed. To achieve oligodendrocyte ablation, transgenic animals were generated that express the herpes virus 1 thymidine kinase (HSV1-TK) gene under the control of the myelin basic protein (MBP) gene promoter. The expression of the MBP-TK transgene in oligodendrocytes is not toxic on its own; however, toxicity can be selectively induced by the systemic injection of animals with nucleoside analogs, such as FIAU [1-(2-deoxy-2-fluoro-beta-delta-arabinofuranosyl)-5-iodouracil]. This system allows us to control the precise duration of the toxic insult and the degree of ablation of oligodendrocytes in vivo. We show that chronic treatment of MBP-TK mice with FIAU during the first 3 postnatal weeks triggers almost a total depletion of oligodendrocytes in the CNS. These effects are accompanied by a behavioral phenotype characterized by tremors, seizures, retarded growth, and premature animal death. We identify the period of highest oligodendrocytes division in the first 9 postnatal days. Delaying the beginning of FIAU treatments results in different degrees of dysmyelination. Dysmyelination in MBP-TK mice is always accompanied by astrocytosis. Thus, this transgenic line provides a model to study the events occurring during dysmyelination of various intensities. It also represents an invaluable tool to investigate remyelination in vivo.
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PMID:A transgenic mouse model for inducible and reversible dysmyelination. 1102 31

Anti-galactocerebroside (anti-GC) antibody has recently been recognized as a possible demyelinating agent. On the 9th day of Mycoplasma pneumoniae (Mp) pneumonia, an 8-year-old boy had a seizure lasting three hours followed by loss of consciousness for 30 hours. Anti-GC antibody titers and myelin basic protein in the CSF were 1:640 and 8.1 ng/dl, respectively. There were no neurological sequelae. It is suggested that the degree of elevation of anti-GC antibody titers in CSF may not correlate well with the severity and neurological prognosis in Mp encephalitis.
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PMID:[A case of Mycoplasma pneumoniae encephalitis with elevated anti-galactocerebroside antibody titers in the cerebrospinal fluid]. 1114 69


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