Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007758 (cerebellar ataxia)
 3,609 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stargazer (stg) mutant mouse, having mutation in stargazin, the calcium channel gamma2 subunit, exhibited several neurological disorders including spontaneous absence seizure, cerebellar ataxia, and head tossing. To understand the molecular pathogenic mechanism of the absence seizure resulted from the loss of stargazin function, the thalamic proteomes between control mouse and stg mouse were compared. We identified 12 proteins expressed differentially (> 1.6-fold) by fluorescence two-dimensional difference gel electrophoresis and tandem mass spectrometry. Six of them are involved in basic metabolism including energy metabolism, three in stress response, two in axonal growth regulation, and one in the endoplasmic reticulum processing. All except mortalin showed decreased level of expression in stg mouse. Two stress-related proteins, mouse stress induced phosphoprotein 1 and peroxiredoxin 6 exhibited reduced levels of expression in stg mouse, while the level of another stress protein, mortalin was increased. Analysis of oxidative protein carbonylation in thalamic proteome of stg mouse showed higher level of carbonylated proteins in stg mouse than in control mouse. Interestingly, down-regulation of stress protein mouse stress induced phosphoprotein 1, metabolic enzyme isovaleryl-CoA dehydrogenase, and the two in neuronal axon growth, collapsin response mediator protein 2 and fascin homolog 1 coincides with the results of our previous study on gamma-butyrolactone-induced transient absence seizure. Our results suggest that the pathogenesis mechanism underlying absence seizure may involve the molecular events contributed by these proteins.
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PMID:Proteomic analysis of stargazer mutant mouse neuronal proteins involved in absence seizure. 1797 78

Studies on animal models of epilepsy and cerebellar ataxia, e.g., stargazer mice (stg) have identified changes in the GABAergic properties of neurones associated with the affected brain loci. Whether these changes contribute to or constitute homeostatic adaptations to a state of altered neuronal excitability is as yet unknown. Using cultured cerebellar granule neurones from control [+/+; alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR)-competent, Kainate receptor (KAR)-competent] and stg (AMPAR-incompetent, KAR-competent), we investigated whether non-NMDA receptor (NMDAR) activity regulates GABA(A) receptor (GABAR) expression. Neurones were maintained in 5 mmol/L KCl-containing basal media or depolarizing media containing either 25 mmol/L KCl or the non-NMDAR agonist kainic acid (KA) (100 micromol/L). KCl- and KA-mediated depolarization down-regulated GABAR alpha1, alpha6 and beta2, but up-regulated alpha4, beta3 and delta subunits in +/+ neurones. The KCl-evoked but not KA-evoked effects were reciprocated in stg neurones compatible with AMPAR-regulation of GABAR expression. Conversely, GABAR gamma2 expression was insensitive to KCl-mediated depolarization, but was down-regulated by KA-treatment in a 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)-reversible manner in +/+ and stg neurones compatible with a KAR-mediated response. KA-mediated up-regulation of GABAR alpha4, beta3 and delta was inhibited by L-type voltage-gated calcium channel (L-VGCC) blockers and the Ca2+/calmodulin-dependent protein kinase inhibitor, 4-[(2S)-2-[(5-isoquinolinylsulfonyl)methylamino]-3-oxo-3-(4-phenyl-1-piperazinyl)propyl] phenyl isoquinoline sulfonic acid ester (KN-62). Up-regulation of GABAR alpha4 and beta3 was also prevented by calcineurin (CaN) inhibitors, FK506 and cyclosporin A. Down-regulation of GABAR alpha1, alpha6 and beta2 was independent of L-VGCC activity, but was prevented by inhibitors of CaN. Thus, we provide evidence that a KAR-mediated and at least three mutually exclusive AMPAR-mediated signalling mechanisms regulate neuronal GABAR expression.
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PMID:AMPA and kainate receptors mediate mutually exclusive effects on GABA(A) receptor expression in cultured mouse cerebellar granule neurones. 1798 25

The stargazer mouse displays cerebellar ataxia and absence epilepsy as a result of a single, recessive mutation on chromosome 15 which silences the expression of the voltage-dependent calcium channel (VDCC) subunit gamma2, termed stargazin. Stargazin is the predominant gamma-subunit expressed in the cerebellum and is essential for correct assembly and trafficking of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-subtype of glutamate receptors (AMPARs) to postsynaptic membranes. As a functional association between AMPARs and VDCCs has been reported, and loss of stargazin results in a loss of AMPA receptors at cerebellar synapses, we investigated whether the loss of stargazin might also change the expression levels of calcium channels at cerebellar synapses. We present data showing that the stargazin mutation affects the expression of postsynaptic L-type Ca(v)1.2 (alpha(1C)-class) but not presynaptic P/Q-type Ca(v)2.1 (alpha(1A)-class) calcium channel proteins at cerebellar synapses. Both Western blot and immunogold analyses demonstrated a significant reduction in the levels of L-type calcium channel Ca(v)1.2 at stargazer cerebellar synapses compared to their non-ataxic littermates. This is in contrast to stargazer hippocampal synapses where no differences were detected in Ca(v)1.2 and 2.1 levels compared to controls, likely due to compensation by subunit gamma8. The loss of L-type calcium channel Ca(v)1.2 at stargazer cerebellar synapses suggests that stargazin mutation may contribute to the loss of VDCCs at postsynaptic sites. It is therefore possible that stargazin is involved in the trafficking of both AMPARs and VDCCs or in the formation of a functional AMPA receptor-calcium channel complex in the postsynaptic membrane.
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PMID:Loss of calcium channels in the cerebellum of the ataxic and epileptic stargazer mutant mouse. 1942 11