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)

The autophagic process was first described in mammalian cells several decades ago. After their formation as double-membraned vacuoles containing cytoplasmic material, autophagic vacuoles or autophagosomes undergo a stepwise maturation including fusion with both endosomal and lysosomal vesicles. However, the molecular mechanisms regulating these fusion steps have begun to emerge only recently. The list of newly discovered molecules that regulate the maturation of autophagosomes to degradative autolysosomes includes the AAA ATPase SKD1, the small GTP binding protein Rab7, and possibly also the Alzheimer-linked presenilin 1. This review combines previous data on the endo/lysosomal fusion steps during autophagic vacuole maturation with recent findings on the molecules regulating these fusion steps. Interestingly, autophagic vacuole maturation appears to be blocked in certain human diseases including neuronal ceroid lipofuscinosis and Danon disease. This suggests that autophagy has important housekeeping or protective functions because a block in autophagic maturation causes a disease.
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PMID:Maturation of autophagic vacuoles in Mammalian cells. 1687 26

In the central nervous system (CNS), a number of different pathological processes such as necrosis, Parkinson's and Alzheimer's diseases are related to disturbance in calcium homeostasis associated with oxidative stress. Here we compare the susceptibility of rat brain plasma membrane Ca(2+)-ATPase (PMCA) and sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) isoforms to in vitro oxidative stress, and investigate a putative role of trifluoperazine (TFP), an antipsychotic drug that is also a powerful inhibitor of Ca(2+)-transporter proteins, in protecting these enzymes. It is shown that, in rat brain, PMCA is very sensitive to the damage induced by preincubation with Fe(2+)-ascorbate, or Fe(2+)-ascorbate plus H2O2, while SERCA is resistant. Inhibition of PMCA activity promoted by Fe(2+)/ascorbate medium is fully prevented by the presence of microM concentrations of either butylated hydroxytoluene (BHT) or TFP, but only partially protected, or reversed, by dithiothreitol (DTT), pointing to some protein cysteine(s) as one of the main targets for a lipid peroxidation-dependent damaging mechanism. However, when 0.5-1 mM H2O2 is added together with Fe(2+)/ascorbate, both BHT and TFP only partially prevent ATPase activity inhibition, and DTT does not confer any protection, suggesting two possible additional mechanisms involving both lipid peroxidation and direct damage to PMCA at amino acid residues other than cysteines. A possible use of micromolar concentrations of TFP as a direct antioxidant protector for PMCA under oxidative stress conditions is discussed.
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PMID:Trifluoperazine protects brain plasma membrane Ca(2+)-ATPase from oxidative damaging. 1695 67

Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders. Although the complex molecular pathophysiology of neurodegeneration is largely unknown, major advances have been achieved by elucidating the genetic defects underlying mendelian forms of these diseases. This has led to the discovery of common pathophysiological pathways such as enhanced oxidative stress, protein misfolding and aggregation and dysfunction of the ubiquitin-proteasome system. Here, we describe loss-of-function mutations in a previously uncharacterized, predominantly neuronal P-type ATPase gene, ATP13A2, underlying an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia (PARK9, Kufor-Rakeb syndrome). Whereas the wild-type protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. Our findings link a class of proteins with unknown function and substrate specificity to the protein networks implicated in neurodegeneration and parkinsonism.
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PMID:Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. 1696 63

Alzheimer disease is a neurological disorder that is characterized by the presence of fibrils and oligomers composed of the amyloid beta (Abeta) peptide. In models of Alzheimer disease, overexpression of molecular chaperones, specifically heat shock protein 70 (Hsp70), suppresses phenotypes related to Abeta aggregation. These observations led to the hypothesis that chaperones might interact with Abeta and block self-association. However, although biochemical evidence to support this model has been collected in other neurodegenerative systems, the interaction between chaperones and Abeta has not been similarly explored. Here, we examine the effects of Hsp70/40 and Hsp90 on Abeta aggregation in vitro. We found that recombinant Hsp70/40 and Hsp90 block Abeta self-assembly and that these chaperones are effective at substoichiometric concentrations (approximately 1:50). The anti-aggregation activity of Hsp70 can be inhibited by a nonhydrolyzable nucleotide analog and encouraged by pharmacological stimulation of its ATPase activity. Finally, we were interested in discerning what type of amyloid structures can be acted upon by these chaperones. To address this question, we added Hsp70/40 and Hsp90 to pre-formed oligomers and fibrils. Based on thioflavin T reactivity, the combination of Hsp70/40 and Hsp90 caused structural changes in oligomers but had little effect on fibrils. These results suggest that if these chaperones are present in the same cellular compartment in which Abeta is produced, Hsp70/40 and Hsp90 may suppress the early stages of self-assembly. Thus, these results are consistent with a model in which pharmacological activation of chaperones might have a favorable therapeutic effect on Alzheimer disease.
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PMID:Heat shock proteins 70 and 90 inhibit early stages of amyloid beta-(1-42) aggregation in vitro. 1697 2

Quinolinic acid (QA) is found at increased concentrations in brain of patients affected by various common neurodegenerative disorders, including Huntington's and Alzheimer's diseases. Considering that the neuropathology of these disorders has been recently attributed at least in part to energy deficit, in the present study we investigated the in vitro effect of QA (0.1-100 microM) on various parameters of energy metabolism, such as glucose uptake, (14)CO(2) production and lactate production, as well as on the activities of the respiratory chain complexes I-V, the citric acid cycle (CAC) enzymes, creatine kinase (CK), lactate dehydrogenase (LDH) and Na(+),K(+)-ATPase and finally the rate of oxygen consumption in brain of 30-day-old rats. We initially observed that QA significantly increased glucose uptake (55%), whereas (14)CO(2) generation from glucose, acetate and citrate was inhibited (up to 60%). Furthermore, QA-induced increase of brain glucose uptake was prevented by the NMDA receptor antagonist MK-801. Complex II activity was also inhibited (up to 35%) by QA, whereas the other activities of the respiratory chain complexes, CAC enzymes, CK and Na(+),K(+)-ATPase were not affected by the acid. Furthermore, inhibition of complex II activity was fully prevented by pre-incubating cortical homogenates with catalase plus superoxide dismutase, indicating that this effect was probably mediated by reactive oxygen species. In addition, lactate production was also not altered by QA, in contrast to the conversion of pyruvate to lactate catalyzed by LDH, which was significantly decreased (17%) by this neurotoxin. We also observed that QA did not change state III, state IV and the respiratory control ratio in the presence of glutamate/malate or succinate, suggesting that its effect on cellular respiration was rather weak. The data provide evidence that QA provokes a mild impairment of brain energy metabolism in vitro and does not support the view that the brain energy deficiency associated to certain neurodegenerative disorders could be solely endorsed to QA accumulation.
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PMID:In vitro effect of quinolinic acid on energy metabolism in brain of young rats. 1712 38

Growing evidence indicates that some metabolites derived from the kynurenine pathway, the major route of L-tryptophan catabolism, are involved in the neurotoxicity associated with several brain disorders, such as Huntington's disease, Parkinson's disease and Alzheimer's disease, as well as in glutaryl-CoA dehydrogenase deficiency (GAI). Considering that the pathophysiology of the brain damage in these neurodegenerative disorders is not completely defined, in the present study, we investigated the in vitro effect of L-kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HA) and anthranilic acid (AA) on some parameters of energy metabolism, namely glucose uptake, 14CO2 production from [U-14C] glucose, [1-14C] acetate and [1,5-14C] citrate, as well as on the activities of the respiratory chain complexes I-IV and Na+,K+-ATPase activity in cerebral cortex from 30-day-old rats. We observed that all compounds tested, except L-kynurenine, significantly increased glucose uptake and inhibited 14CO2 production from [U-14C] glucose, [1-14C] acetate and [1,5-14C] citrate. In addition, the activities of complexes I, II and IV of the respiratory chain were significantly inhibited by 3HK, while 3HA inhibited complexes I and II activities and AA inhibited complexes I-III activities. Moreover, Na+,K+-ATPase activity was not modified by these kynurenines. Taken together, our present data provide evidence that various kynurenine intermediates provoke impairment of brain energy metabolism.
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PMID:Kynurenines impair energy metabolism in rat cerebral cortex. 1715 44

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

Strong evidence suggests a mechanistic link between cholesterol metabolism and the formation of amyloid-beta peptides, the principal constituents of senile plaques found in the brains of patients with Alzheimer's disease. Here, we show that several fibrates and diaryl heterocycle cyclooxygenase inhibitors, among them the commonly used drugs fenofibrate and celecoxib, exhibit effects similar to those of cholesterol on cellular membranes and amyloid precursor protein (APP) processing. These drugs have the same effects on membrane rigidity as cholesterol, monitored here by an increase in fluorescence anisotropy. The effect of the drugs on cellular membranes was also reflected in the inhibitory action on the sarco(endo)plasmic reticulum Ca(2+)-ATPase, which is known to be inhibited by excess ordering of membrane lipids. The drug-induced decrease of membrane fluidity correlated with an increased association of APP and its beta-site cleaving enzyme BACE1 with detergent-resistant membranes (DRMs), which represent membrane clusters of substantial rigidity. DRMs are hypothesized to serve as platforms for the amyloidogenic processing of APP. According to this hypothesis, both cholesterol and the examined compounds stimulated the beta-secretase cleavage of APP, resulting in a massive increase of secreted amyloid-beta peptides. The membrane-ordering potential of the drugs was observed in a cell-free assay, suggesting that the amyloid-beta promoting effect was analog to cholesterol due to primary effect on membrane rigidity. Because fenofibrate and celecoxib are widely used in humans as hypolipidemic drugs for prevention of atherosclerosis and as anti-inflammatory drugs against arthritis, possible side effects should be considered upon long-term clinical application.
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PMID:Cholesterol-like effects of selective cyclooxygenase inhibitors and fibrates on cellular membranes and amyloid-beta production. 1739 89

Dysregulation of the proteasome has been documented in a variety of human diseases such as Alzheimer, muscle atrophy, cataracts etc. Proteolytic activity of 26 S proteasome is ATP- and ubiquitin-dependent. O-GlcNAcylation of Rpt2, one of the AAA ATPases in the 19 S regulatory cap, shuts off the proteasome through the inhibition of ATPase activity. Thus, through control of the flux of glucose into O-GlcNAc, the function of the proteasome is coupled to glucose metabolism. In the present study we found another metabolic control of the proteasome via cAMP-dependent protein kinase (PKA). Contrary to O-Glc-NAcylation, PKA activated proteasomes both in vitro and in vivo in association with the phosphorylation at Ser(120) of another AAA ATPase subunit, Rpt6. Mutation of Ser(120) to Ala blocked proteasome function. The stimulatory effect of PKA and the phosphorylation of Rpt6 were reversible by protein phosphatase 1 gamma. Thus, hormones using the PKA system can also regulate proteasomes often in concert with glucose metabolism. This finding might lead to novel strategies for the treatment of proteasome-related diseases.
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PMID:Proteasome function is regulated by cyclic AMP-dependent protein kinase through phosphorylation of Rpt6. 1756 87

To elucidate mechanism of ganglioside neuroprotection, it is important to study their metabolic effects, specifically of action on Na+, K+ -ATPase. It has been shown that under effect of oxidative stress inductors and neurotoxins an oxidative inactivation of this enzyme takes place in PC12 cells and brain cortex synaptosomes, this inactivation being able to be prevented or decreased by ganglioside GM1. Thus, for instance, 24 h after action of 1 mM H2O2, activity of Na+, K+ -ATPase in PC12 cells decreased more than twice. However, in the case of preincubation of the cells with ganglioside GM1 prior to the H2O2 action this enzyme activity did not differ statistically significantly from control. Ganglioside GM1 also was able to increase significantly the enzyme activity decreased by action on the PC12 cells of amyloid beta-peptide (AP) causing lesion of neurons in Alzheimer's disease and at low H202 concentrations. Experiments on brain cortex synaptosomes have established that not only antioxidants--alpha-tocopherol and superoxide dismutase--but also ganglioside GM1 prevent the glutamateproduced Na+, K+ -ATPase oxidative inactivation. The obtained data agree with a suggestion that the ganglioside neuroprotective effect at action on nerve cells of such toxins as Abeta, glutamate or reactive oxygen species is due to their ability to inhibit the free-radical reactions.
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PMID:[Effects of oxidative stress inducers, neurotoxins, and ganglioside GM1 on Na+, K+-ATPase in PC12 and brain synaptosomes]. 1767 7


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