Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tolerance and dependence induced by chronic delta-9-tetrahydrocannabinol (THC) administration were investigated in mice. The effects on body weight, analgesia and hypothermia were measured during 6 days of treatment (10 or 20 mg kg(-1) THC twice daily). A rapid tolerance to the acute effects was observed from the second THC administration. The selective CB-1 receptor antagonist SR 141716A (10 mg kg(-1)) was administered at the end of the treatment, and somatic and vegetative manifestations of abstinence were evaluated. SR 141716A administration precipitated several somatic signs that included wet dog shakes, frontpaw tremor, ataxia, hunched posture, tremor, ptosis, piloerection, decreased locomotor activity and mastication, which can be interpreted as being part of a withdrawal syndrome. Brains were removed immediately after the behavioural measures and assayed for adenylyl cyclase activity. An increase in basal, forskolin and calcium/calmodulin stimulated adenylyl cyclase activities was specifically observed in the cerebellum of these mice. The motivational effects of THC administration and withdrawal were evaluated by using the place conditioning paradigm. No conditioned change in preference to withdrawal associated environment was observed. In contrast, a conditioned place aversion was produced by the repeated pairing of THC (20 mg kg(-1)), without observing place preference at any of the doses used. This study constitutes a clear behavioural and biochemical model of physical THC withdrawal with no motivational aversive consequences. This model permits an easy quantification of THC abstinence in mice and can be useful for the elucidation of the molecular mechanisms involved in cannabinoid dependence.
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PMID:Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with delta-9-tetrahydrocannabinol. 988 86

Familial hemiplegic migraine (HM) is an autosomal dominant migraine with aura. In 20% of HM families, HM is associated with a mild permanent cerebellar ataxia (PCA). The CACNA1A gene encoding the alpha1A subunit of P/Q-type voltage-gated calcium channels is involved in 50% of unselected HM families and in all families with HM/PCA. Four CACNA1A missense mutations have been identified in HM: two in pure HM and two in HM/PCA. Different CACNA1A mutations have been identified in other autosomal dominant conditions: mutations leading to a truncated protein in episodic ataxia type 2 (EA2), small expansions of a CAG trinucleotide in spinocerebellar ataxia type 6 and also in three families with EA2 features, and, finally, a missense mutation in a single family suffering from episodic ataxia and severe progressive PCA. We screened 16 families and 3 nonfamilial case patients affected by HM/PCA for specific CACNA1A mutations and found nine families and one nonfamilial case with the same T666M mutation, one new mutation (D715E) in one family, and no CAG repeat expansion. Both T666M and D715E substitutions were absent in 12 probands belonging to pure HM families whose disease appears to be linked to CACNA1A. Finally, haplotyping with neighboring markers suggested that T666M arose through recurrent mutational events. These data could indicate that the PCA observed in 20% of HM families results from specific pathophysiologic mechanisms.
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PMID:Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. 991 47

A fundamental question in brain development is how neurons make the precise topographic connections necessary for function. The hypothesis that transient expression of calcium (Ca2+) signaling molecules may have a role in this process was tested by studying human cerebella at midgestation. In addition, four adult brains, two controls and two from patients with ataxia, were studied as well. The temporal and spatial distribution of intracellular Ca2+ channel/receptors, inositol trisphosphate receptor type 1 (IP3R1) and ryanodine receptor (RyR) and three Ca2+ binding proteins were examined with immunocytochemical methods. A positive immune reaction with all markers of Ca2+ signaling was found in the Purkinje cell layer starting from 17 g.w. (gestational weeks), the youngest age studied. The immune reactions were not homogeneous throughout the extent of the Purkinje cell layer, but instead displayed a 'patchy' appearance in all intrauterine stages. In the adult cerebellum the expression of Ca2+ signaling molecules was homogenous. In the two cerebella obtained from patients suffering from ataxia, a several-fold reduction of immunostaining with IP3R1 was found. Our findings suggest that transient and differential mobilization of intracellular Ca2+ in seemingly homogenous neuronal types may play a role in development of highly organized projection maps of the cerebellar cortex. Moreover, lack of IP3R1 in the diseased brains suggests that internal stores of Ca2+ play an important role in normal function of the cerebellum.
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PMID:Calcium signaling molecules in human cerebellum at midgestation and in ataxia. 1021 89

Spinocerebellar ataxia type 6 (SCA6, MIM 183086) is an autosomal dominant spinocerebellar degeneration. Mild expansion of a CAG repeat in voltage-dependent Ca2+ channel alpha 1A subunit (CACNL1A) gene, which was predicted to encode a polyglutamine tract, has been identified as a causative mutation for SCA6. SCA6 is one of the common subtypes of spinocerebellar degeneration, accounting for approximately 12% in the dominantly inherited ataxias in Japan. Mean age at onset in the SCA6 patients is 52 years, which is much later than those reported for other autosomal dominant ataxias including SCA1, SCA2, Machado-Joseph disease, and dentatorubral-pallidoluysian atrophy. Anticipation in SCA6 is quite mild. The size of expanded CAG repeats ranged 21 to 26 repeats and was found to be correlated inversely with age at onset in patients with SCA6. Ataxia is most common and cardinal clinical features in SCA6. Patients with a prolonged clinical course, however, show other accompanying clinical features including dystonic postures, involuntary movements, and abnormalities in tendon reflexes. Investigations of the mechanisms of neuronal death in the cerebellum, in particular relation to the impaired function of the voltage-dependent Ca2+ channel and the toxic effects of expanded polyglutamine tracts, will be indispensable for the development of therapeutic measures for SCA6.
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PMID:[Molecular and clinical features in spinocerebellar ataxia type 6 (SCA6) in Japanese]. 1022 85

P-type and Q-type calcium channels mediate neurotransmitter release at many synapses in the mammalian nervous system. The alpha 1A calcium channel has been implicated in the etiologies of conditions such as episodic ataxia, epilepsy and familial migraine, and shares several properties with native P- and Q-type channels. However, the exact relationship between alpha 1A and P- and Q-type channels is unknown. Here we report that alternative splicing of the alpha 1A subunit gene results in channels with distinct kinetic, pharmacological and modulatory properties. Overall, the results indicate that alternative splicing of the alpha 1A gene generates P-type and Q-type channels as well as multiple phenotypic variants.
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PMID:Splicing of alpha 1A subunit gene generates phenotypic variants of P- and Q-type calcium channels. 1032 Dec 43

Diisopropyl phosphorofluoridate (DFP) produces organophosphorus ester-induced delayed neurotoxicity (OPIDN) in hen, human, and other sensitive species. This is characterized by mild ataxia, which progresses to severe ataxia or paralysis in a few days. Ultrastructurally, OPIDN is associated with the degeneration of axons in central and peripheral nervous systems. Bacterially expressed longest human tau protein (htau40) phosphorylated by DFP-treated hen brain supernatant showed a decrease in microtubule binding in a shorter time than that phosphorylated by control hen brain supernatant. The decrease in htau40-microtubule binding observed on htau40 phosphorylation by the recombinant Ca2+/calmodulin (CaM)-dependent protein kinase II (CaM kinase II) alpha-subunit showed that CaM kinase II present in brain supernatant could participate in tau phosphorylation even in the absence of Ca2+/CaM and decrease tau-microtubule binding. In addition, use of htau40 mutants, htau40m1 (Ala416) and htau40m6 (Asp416), suggested that replacement of Ser416 by neutral or acidic amino acid produced some change in htau40 conformation that caused diminished binding with microtubules phosphorylated by brain supernatant in the presence of ethylene glycol bis(beta-aminoethyl ether) N, N'tetraacetic acid (EGTA). The change in conformation produced by Ser416 phosphorylation, however, was different from that produced by mutants since only nonmutated htau40 showed a significant decrease in binding with microtubules on phosphorylation by recombinant CaM kinase II in the presence of Ca2+/CaM compared to that obtained by phosphorylation in the presence of EGTA. This study showed that enhanced Ca2+/CaM-dependent protein kinase activity in DFP-treated hen brain supernatant may cause decreased tau-microtubule binding and destabilization of microtubules and may be involved in axonal degeneration in OPIDN.
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PMID:Tau phosphorylation by diisopropyl phosphorofluoridate (DFP)-treated hen brain supernatant inhibits its binding with microtubules: role of Ca2+/Calmodulin-dependent protein kinase II in tau phosphorylation. 1032 22

The recent discovery that familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6 are allelic disorders caused by different mutations in CACNA1A, a calcium-channel-encoding gene, adds to a growing list of channelopathies causing paroxysmal neurologic disturbance and progressive neurodegeneration. Calcium channelopathies in the central nervous system provide a model to study the important roles that calcium channels play in neuronal function.
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PMID:Calcium channelopathies in the central nervous system. 1039 79

The P/Q type Ca2+ channel alpha 1-subunit (CACN1A4) gene on chromosome 19p13 is a promising candidate susceptibility locus for schizophrenia. Point mutations in CACN1A4 cause familial hemiplegic migraine and episodic ataxia. Expansion in a coding 3' CAG repeat causes spino-cerebellar ataxia type 6 (SCA6). The mouse mutant phenotype totterer has a form of petit-mal epilepsy. These are neurological conditions, all of which exhibit features in common with schizophrenia. The 19p13 area is also paralogous to other genomic regions of interest in schizophrenia genetics. For these reasons, we performed an association study with the CAG repeat and schizophrenia using 225 Scottish schizophrenia and 198 unrelated Scottish controls. The repeat was not associated with the disorder (P = 0.72) and neither did the schizophrenics have significantly longer alleles than the controls (P = 0.45). We conclude that the SCA6 CAG repeat is not associated with schizophrenia susceptibility. However, it remains possible that other variants in the region could be involved.
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PMID:Association study of the CACN1A4 (SCA6) triplet repeat and schizophrenia. 1041 93

Cytoplasmic calcium, which acts as a second messenger, is derived not only from outside the cell but also from intracellular stores. A receptor for inositol 1,4,5-trisphosphate (IP3), an intracellular second messenger, is located on these internal calcium stores and functions as a calcium releasing channel. The "type 1" IP3 receptor (IP3R1) is concentrated predominantly in cerebellar Purkinje cells and is also widely present in other neural and peripheral tissues, but many of its physiological roles in these cells are still unclear. We have previously succeeded in obtaining mice with disruption of this IP3R1 gene, in which brain IP3-induced calcium release was almost completely abolished. They were rarely born alive, indicating that IP3R1 has some functions during embryonic development. Animals exhibited severe neurological symptoms, ataxia and epilepsy, and were shown to be deficient in the cerebellar long-term depression. They give us promising clues regarding the physiological roles of calcium release from internal stores and serve as a model for the relevant human disease states.
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PMID:Type 1 inositol 1,4,5-trisphosphate receptor knock-out mice: their phenotypes and their meaning in neuroscience and clinical practice. 1042 89

In recent years, genetic defects of the mitochondrial genome (mtDNA) were shown to be associated with a heterogeneous group of disorders, known as mitochondrial diseases, but the cellular events deriving from the molecular lesions and the mechanistic basis of the specificity of the syndromes are still incompletely understood. Mitochondrial calcium (Ca2+) homeostasis depends on close contacts with the endoplasmic reticulum and is essential in modulating organelle function. Given the strong dependence of mitochondrial Ca2+ uptake on the membrane potential and the intracellular distribution of the organelle, both of which may be altered in mitochondrial diseases, we investigated the occurrence of defects in mitochondrial Ca2+ handling in living cells with either the tRNALys mutation of MERRF (myoclonic epilepsy with ragged-red fibers) or the ATPase mutation of NARP (neurogenic muscle weakness, ataxia and retinitis pigmentosa). There was a derangement of mitochondrial Ca2+ homeostasis in MERRF, but not in NARP cells, whereas cytosolic Ca2+ responses were normal in both cell types. Treatment of MERRF cells with drugs affecting organellar Ca2+ transport mostly restored both the agonist-dependent mitochondrial Ca2+ uptake and the ensuing stimulation of ATP production. These results emphasize the differences in the cellular pathogenesis of the various mtDNA defects and indicate specific pharmacological approaches to the treatment of some mitochondrial diseases.
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PMID:A calcium signaling defect in the pathogenesis of a mitochondrial DNA inherited oxidative phosphorylation deficiency. 1042 22


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