Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lesch-Nyhan disease (LND) is a rare disorder caused by a defect of an enzyme in the purine salvage pathway, hypoxanthine phosphoribosyl transferase (HPRT). It is still unknown how the metabolic defect translates into the complex neuropsychiatric phenotype characterized by self-injurious behavior, dystonia and mental retardation. There are abnormalities in purine and pyrimidine nucleotide content in HPRT-deficient cells. We hypothesized that altered nucleotide concentrations in HPRT deficiency change G-protein-mediated signal transduction. Therefore, our original study aim was to examine the high-affinity GTPase activity of G-proteins in membranes from primary human skin and immortalized mouse skin fibroblasts, rat B103 neuroblastoma cells and mouse Neuro-2a neuroblastoma cells. Unexpectedly, in membranes from human fibroblasts, B103- and Neuro-2a cells, V(max) of low-affinity nucleoside 5'-triphosphatase (NTPase) activities was decreased up to 7-fold in HPRT deficiency. In contrast, in membranes from mouse fibroblasts, HPRT deficiency increased NTPase activity up to 4-fold. The various systems analyzed differed from each other in terms of K(m) values for NTPs, absolute V(max) values and K(i) values for nucleoside 5'-[beta,gamma-imido]triphosphates. Our data show that altered membrane NTPase activity is a biochemical hallmark of HPRT deficiency, but species and cell-type differences have to be considered. Thus, future studies on biochemical changes in LND should be conducted in parallel in several HPRT-deficient systems.
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PMID:Altered membrane NTPase activity in Lesch-Nyhan disease fibroblasts: comparison with HPRT knockout mice and HPRT-deficient cell lines. 1593 74

We report on a 38-year-old patient with rapid-onset dystonia-parkinsonism (RDP) with a missense mutation in the Na/K-ATPase alpha3 subunit (ATP1A3). Asymmetrical parkinsonian symptoms evolved over a year. After a stable episode of another 2.5 years, overnight he developed oromandibular dystonia and more severe parkinsonian symptoms. We conclude that RDP should be considered as a rare cause of levodopa-unresponsive parkinsonism even if there is no family history and the classic presentation is lacking.
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PMID:Sporadic rapid-onset dystonia-parkinsonism presenting as Parkinson's disease. 1616 Nov 39

Rapid-onset dystonia-parkinsonism (RDP, DYT12) is one of the fifteen genetic types of dystonia. Its' transmission is autosomal dominant with reduced penetrance. Onset of RDP is abrupt and occurring usually in the second decade of life, sometimes with preceding transient episods of dystonia. Clinical course of the disease is stationary, but the disease in most of the cases leads to seroius neurololgic disability. Previous haplotypic analyses have shown that RDP is linked to markers on chromosome 19q13. The last year it was found that the mutated gene is the one for the NA+/K(+)-ATPase alpha3 subunit (ATP1A3), (one of the sodium pumps). One of the six families described so far was identified in Poland.
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PMID:[Rapid-onset dystonia-parkinsonism]. 1651 24

The Na(+),K(+)-ATPase plays key roles in brain function. Recently, missense mutations in the Na(+),K(+)-ATPase were found associated with familial rapid-onset dystonia parkinsonism (FRDP). Here, we have characterized the functional consequences of FRDP mutations Phe785Leu and Thr618Met. Both mutations lead to functionally altered, but active, Na(+),K(+)-pumps, that display reduced apparent affinity for cytoplasmic Na(+), but the underlying mechanism differs between the mutants. In Phe785Leu, the interaction of the E(1) form with Na(+) is defective, and the E(1)-E(2) equilibrium is not displaced. In Thr618Met, the Na(+) affinity is reduced because of displacement of the conformational equilibrium in favor of the K(+)-occluded E(2)(K(2)) form. In both mutants, K(+) interaction at the external activating sites of the E(2)P phosphoenzyme is normal. The change of cellular Na(+) homeostasis is likely a major factor contributing to the development of FRDP in patients carrying the Phe785Leu or Thr618Met mutation. Phe785Leu moreover interferes with Na(+) interaction on the extracellular side and reduces the affinity for ouabain significantly. Analysis of two additional Phe(785) mutants, Phe785Leu/Leu786Phe and Phe785Tyr, demonstrated that the aromatic function of the side chain, as well as its exact position, is critical for Na(+) and ouabain binding. The effects of substituting Phe(785) could be explained by structural modeling, demonstrating that Phe(785) participates in a hydrophobic network between three transmembrane segments. Thr(618) is located in the cytoplasmic part of the molecule near the catalytic site, and the structural modeling indicates that the Thr618Met mutation interferes with the bonding pattern in the catalytic site in the E(1) form, thereby destabilizing E(1) relative to E(2)(K(2)).
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PMID:Mutations Phe785Leu and Thr618Met in Na+,K+-ATPase, associated with familial rapid-onset dystonia parkinsonism, interfere with Na+ interaction by distinct mechanisms. 1663 66

The DeltaGAG deletion mutation in DYT1, causing a loss of a glutamic acid near the carboxyl terminus of torsinA protein (torsinADeltaE), is dominantly inherited and tends to result in a severe generalized form of dystonia with childhood onset. We have used a yeast two-hybrid interaction assay to examine torsinA and its mutant torsinADeltaE interactions. Our data showed that torsinA monomers are capable of interacting with themselves and that mutant torsinADeltaE fails to interact with itself or with torsinA. We also demonstrated that purified torsinA protein is an ATPase, which forms a multimeric complex in vitro and that the DeltaGAG mutation disrupts the formation of multimeric complex and decreases torsinA's ATPase activity.
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PMID:Molecular defects of the dystonia-causing torsinA mutation. 1704 61

The genetically dystonic (dt) rat, an autosomal recessive model of generalized dystonia, harbors an insertional mutation in Atcay. As a result, dt rats are deficient in Atcay transcript and the neuronally-restricted protein caytaxin. Previous electrophysiological and biochemical studies have defined olivocerebellar pathways, particularly the climbing fiber projection to Purkinje cells, as sites of significant functional abnormality in dt rats. In normal rats, Atcay transcript is abundantly expressed in the granular and Purkinje cell layers of cerebellar cortex. To better understand the consequences of caytaxin deficiency in cerebellar cortex, differential gene expression was examined in dt rats and their normal littermates. Data from oligonucleotide microarrays and quantitative real-time reverse transcriptase-PCR (QRT-PCR) identified phosphatidylinositol signaling pathways, calcium homeostasis, and extracellular matrix interactions as domains of cellular dysfunction in dt rats. In dt rats, genes encoding the corticotropin-releasing hormone receptor 1 (CRH-R1, Crhr1) and plasma membrane calcium-dependent ATPase 4 (PMCA4, Atp2b4) showed the greatest up-regulation with QRT-PCR. Immunocytochemical experiments demonstrated that CRH-R1, CRH, and PMCA4 were up-regulated in cerebellar cortex of mutant rats. Along with previous electrophysiological and pharmacological studies, our data indicate that caytaxin plays a critical role in the molecular response of Purkinje cells to climbing fiber input. Caytaxin may also contribute to maturational events in cerebellar cortex.
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PMID:Caytaxin deficiency disrupts signaling pathways in cerebellar cortex. 1709 53

Several disorders have been associated with mutations in Na,K-ATPase alpha isoforms (rapid-onset dystonia parkinsonism, familial hemiplegic migraine type-2), as well as reduction in Na,K-ATPase content (depression and Alzheimer's disease), thereby raising the issue of whether haploinsufficiency or altered enzymatic function contribute to disease etiology. Three isoforms are expressed in the brain: the alpha1 isoform is found in many cell types, the alpha2 isoform is predominantly expressed in astrocytes, and the alpha3 isoform is exclusively expressed in neurons. Here we show that mice heterozygous for the alpha2 isoform display increased anxiety-related behavior, reduced locomotor activity, and impaired spatial learning in the Morris water maze. Mice heterozygous for the alpha3 isoform displayed spatial learning and memory deficits unrelated to differences in cued learning in the Morris maze, increased locomotor activity, an increased locomotor response to methamphetamine, and a 40% reduction in hippocampal NMDA receptor expression. In contrast, heterozygous alpha1 isoform mice showed increased locomotor response to methamphetamine and increased basal and stimulated corticosterone in plasma. The learning and memory deficits observed in the alpha2 and alpha3 heterozygous mice reveal the Na,K-ATPase to be an important factor in the functioning of pathways associated with spatial learning. The neurobehavioral changes seen in heterozygous mice suggest that these mouse models may be useful in future investigations of the associated human CNS disorders.
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PMID:Deficiency in Na,K-ATPase alpha isoform genes alters spatial learning, motor activity, and anxiety in mice. 1723 93

The authors report a 7-year follow-up video study and molecular data on the Irish rapid-onset dystonia-Parkinsonism kindred. All affected patients tested had a missense mutation in the Na(+)/K(+) -ATPase alpha3 subunit (ATP1A3), twice previously identified, suggestive of a mutation hotspot. Clinical presentation, progression, and outcome in this kindred is varied. Some patients remain stable over many years, others worsen, have a fluctuating course, or improve over time. To date there have been no effective treatments for this disorder, although Na(+)/K(+) ATPase may be a future therapeutic target. The broad phenotypic spectrum of RDP described in the text and detailed in the video, should be considered when evaluating patients with dystonia.
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PMID:Heterogeneity of presentation and outcome in the Irish rapid-onset dystonia-parkinsonism kindred. 1751 73

The Na,K-ATPase is composed of multiple isoforms and the isoform distribution varies with the tissue and during development. The alpha1 isoform for example, is the major isoform in the kidney and many other tissues, while the alpha2 isoform is the predominate one in skeletal muscle. All three isoforms are found in the brain although in adult rodent brain, the alpha 3 isoform is located essentially in neurons while the alpha2 isoform is found in astrocytes and some limited neuronal populations. Interestingly the alpha 4 isoform is found exclusively in the mid region of the sperm tail. The distribution of the isoforms of the Na,K-ATPase has been extensively studied in many tissues and during development. The examples cited above provide some indication to the diversity of Na,K-ATPase isoform expression. In order to understand the significance of this distribution, we have developed animals which lack the alpha1, alpha2, and alpha 3 isoforms. It is anticipated that these studies will provide insight into the role that these isoforms play in driving various biological processes in specific tissues. Here we describe some of our studies which deal with the behavioral aspects of the alpha1, alpha2, and alpha 3 deficient mice, particularly those that are haploinsufficient in one isoform i.e. lacking one functional gene for the alpha1, alpha2, or alpha 3 isoforms. Such studies are important as two human diseases are associated with deficiency in the alpha2 and alpha 3 isoforms. These are Familial Hemiplegic Migraine type 2 and Rapid-Onset Dystonia Parkinsonism, these diseases result from alpha2 and alpha 3 isoform haploinsufficiency, respectively. We find that the haploinsufficiency of both alpha2 and alpha 3 isoforms result in behavioral defects.
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PMID:Na,K-ATPase and the role of alpha isoforms in behavior. 1804 13

The loss of a glutamic acid residue in the AAA-ATPase (ATPases associated with diverse cellular activities) torsinA is responsible for most cases of early onset autosomal dominant primary dystonia. In this study, we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA. Snapin co-localized with endogenous torsinA on dense core granules in PC12 cells and was recruited to perinuclear inclusions containing mutant DeltaE-torsinA in neuroblastoma SH-SY5Y cells. In view of these observations, synaptic vesicle recycling was analyzed using the lipophilic dye FM1-43 and an antibody directed against an intravesicular epitope of synaptotagmin I. We found that overexpression of wild type torsinA negatively affects synaptic vesicle endocytosis. Conversely, overexpression of DeltaE-torsinA in neuroblastoma cells increases FM1-43 uptake. Knockdown of snapin and/or torsinA using small interfering RNAs had a similar inhibitory effect on the exo-endocytic process. In addition, down-regulation of torsinA causes the persistence of synaptotagmin I on the plasma membrane, which closely resembles the effect observed by the overexpression of the DeltaE-torsinA mutant. Altogether, these findings suggest that torsinA plays a role together with snapin in regulated exocytosis and that DeltaE-torsinA exerts its pathological effects through a loss of function mechanism. This may affect neuronal uptake of neurotransmitters, such as dopamine, playing a role in the development of dystonic movements.
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PMID:The dystonia-associated protein torsinA modulates synaptic vesicle recycling. 1816 55


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