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1.
Arch Neurol ; 66(1): 97-101, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19139306

ABSTRACT

BACKGROUND: Episodic ataxia (EA) is variably associated with additional neurologic symptoms. At least 4 genes have been implicated. Recently, a mutation in the SLC1A3 gene encoding the glutamate transporter EAAT1 was identified in a patient with severe episodic and progressive ataxia, seizures, alternating hemiplegia, and migraine headache. The mutant EAAT1 showed severely reduced uptake of glutamate. The syndrome was designated EA6 and shares overlapping clinical features with EA2, which is caused by mutations in CACNA1A. OBJECTIVE: To test the role of the SLC1A3 gene in EA. DESIGN: Genetic and functional studies. We analyzed the coding region of the SLC1A3 gene by direct sequencing. SETTING: Academic research. PATIENTS: DNA samples from 20 patients with EA (with or without interictal nystagmus) negative for CACNA1A mutations were analyzed. MAIN OUTCOME MEASURES: We identified 1 novel EAAT1 mutation in a family with EA and studied the functional consequences of this mutation using glutamate uptake assay. RESULTS: We identified a missense C186S mutation that segregated with EA in 3 family members. The mutant EAAT1 showed a modest but significant reduction of glutamate uptake. CONCLUSIONS: We broadened the clinical spectrum associated with SLC1A3 mutations to include milder manifestations of EA without seizures or alternating hemiplegia. The severity of EA6 symptoms appears to be correlated with the extent of glutamate transporter dysfunction.


Subject(s)
Excitatory Amino Acid Transporter 1/genetics , Genetic Predisposition to Disease/genetics , Glutamic Acid/metabolism , Mutation/genetics , Spinocerebellar Degenerations/genetics , Spinocerebellar Degenerations/metabolism , Adult , Brain Chemistry/genetics , Cerebellum/metabolism , Cerebellum/physiopathology , DNA Mutational Analysis , Female , Genetic Markers/genetics , Genetic Testing , Genotype , Hemiplegia/genetics , Hemiplegia/physiopathology , Humans , Inheritance Patterns/genetics , Male , Middle Aged , Migraine Disorders/genetics , Migraine Disorders/physiopathology , Pedigree , Phenotype , Seizures/genetics , Seizures/physiopathology , Spinocerebellar Degenerations/physiopathology
2.
Neurochem Int ; 42(4): 345-51, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12470708

ABSTRACT

Central Glia-4 (CG-4) glioma cells exhibit Na(+)-dependent glutamate uptake, and mRNA for each of the GLT, GLAST, and EAAC glutamate transporters was found in the cells by RT-PCR. However, GLT protein in CG-4 cells was not detected by Western blotting. The Wnt-1 oncogene markedly decreased the expression of the mRNAs for GLT and GLAST glutamate transporters in CG-4 glioma cells. This effect of Wnt-1 is in direct contrast to its previously published effects on C6 astrocytoma cells where Wnt-1 induces the expression of GLT, but not protein, and on PC12 pheochromocytoma cells where Wnt-1 induces GLAST. We suggest that these differences in the ability of Wnt-1 to induce or repress GLT and GLAST are due to differences in Wnt-1 dosages or Wnt-1-induced signaling pathways in these cells. The abnormal translation of the GLT RNA in Wnt-1-expressing C6 cells was ascribed to some abnormality in the processing of the GLT transcript. Consistent with this idea is the finding that GLT mRNA was translated in Wnt-1-expressing C6 cells when the GLT mRNA required no splicing before translation occurred.


Subject(s)
Amino Acid Transport System X-AG/biosynthesis , Excitatory Amino Acid Transporter 2/biosynthesis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/physiology , Zebrafish Proteins , Animals , Aspartic Acid/metabolism , Blotting, Western , Cell Line , Cells, Cultured , DNA, Complementary/genetics , DNA, Complementary/metabolism , PC12 Cells , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Transfection , Wnt Proteins , Wnt1 Protein
3.
Oncogene ; 21(41): 6348-55, 2002 Sep 12.
Article in English | MEDLINE | ID: mdl-12214275

ABSTRACT

Wnt-1 and Wnt-3a exhibit redundancy in neural crest development. We have found that they do not produce the same effects on PC12 cells, which were obtained from the adrenal medulla, a neural crest derivative. However, both Wnt-1 or Wnt-3a inhibit nerve growth factor (NGF)-induced neurite outgrowth. The inhibition is reversed by the protein kinase C (PKC) inhibitor, bisindolylmaleimide-I, but it did not reverse Wnt-1-induced activation of the canonical Wnt pathway. The Wnt-1 inhibitory effect was not reversed by several other PKC inhibitors, by phorbol ester-induced down-regulation of PKC, or by pertussis toxin, which is known to inhibit another Wnt signaling pathway, the Wnt/Ca(2+) pathway. We suggest that bisindolylmaleimide-I acts by affecting either a pathway downstream from Lef-1/Tcf in the canonical pathway or a Wnt signaling pathway other than the canonical pathway. In either case, the bisindolylmaleimide-I sensitivity of this pathway should aid in its identification.


Subject(s)
Cell Differentiation/drug effects , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Maleimides/pharmacology , Nerve Growth Factor/pharmacology , Protein Biosynthesis , Proto-Oncogene Proteins/biosynthesis , Zebrafish Proteins , Animals , Cell Differentiation/genetics , Drug Antagonism , PC12 Cells , Protein Kinase C/antagonists & inhibitors , Proteins/genetics , Proto-Oncogene Proteins/genetics , Rats , Signal Transduction/drug effects , Signal Transduction/genetics , Wnt Proteins , Wnt1 Protein , Wnt3 Protein
4.
Brain Res Dev Brain Res ; 136(2): 101-10, 2002 Jun 30.
Article in English | MEDLINE | ID: mdl-12101027

ABSTRACT

The protein neuronatin is expressed in the nervous system of the fetus and neonate at a much higher level than in the adult. Its function is unknown. As a result of variable splicing, neuronatin mRNA exists in two forms, alpha and beta. Wild type PC12 cells express neuronatin-alpha. We have isolated a PC12 variant, called 1.9, that retains many of the neuron-like properties of wild type PC12 cells, but it does not express neuronatin and it exhibits markedly increased sensitivity to the toxic effects of nigericin, rotenone and valinomycin. Pretreatment of the 1.9 cells with alpha-methyltyrosine, which inhibits dopamine synthesis, had little effect on the cells' sensitivity to nigericin, rotenone or valinomycin indicating that dopamine-induced oxidative stress was not involved in the toxicity of these compounds. However, flattened cell subvariants of the 1.9 cells, which do not have any neuron-specific characteristics, did not exhibit increased sensitivity to nigericin indicating that some neuronal characteristic of the 1.9 cells contributed to the toxicity of nigericin. After the neuronatin-beta gene was transfected into and expressed in the 1.9 cells, they regained wild type PC12 levels of resistance to nigericin, rotenone and valinomycin. These studies suggest that the function of neuronatin during development could be to protect developing cells from toxic insult occurring during that period.


Subject(s)
Animals, Newborn/metabolism , Brain/metabolism , Cell Death/genetics , Drug Resistance/genetics , Fetus/metabolism , Membrane Proteins/metabolism , Membrane Transport Proteins , Nerve Tissue Proteins/metabolism , Neurotoxins/metabolism , Animals , Animals, Newborn/growth & development , Brain/embryology , Brain/growth & development , Carrier Proteins/drug effects , Carrier Proteins/metabolism , Catecholamine Plasma Membrane Transport Proteins , Cell Death/drug effects , Cell Differentiation/physiology , Cell Size/drug effects , Cell Size/physiology , Culture Media, Conditioned/pharmacology , Dopamine/metabolism , Fetus/embryology , Gene Expression Regulation, Developmental/physiology , Ionophores/pharmacology , Melanins/metabolism , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Neurons/drug effects , Neurons/metabolism , Neurons/ultrastructure , Nigericin/pharmacology , Oxidative Stress/drug effects , Oxidative Stress/physiology , PC12 Cells , Rats , Reactive Oxygen Species/metabolism , Rotenone/pharmacology , Uncoupling Agents/pharmacology , Valinomycin/pharmacology , alpha-Methyltyrosine/pharmacology
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