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Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this article is to emphasize the important role that copper plays in the function of nerve cells. We are reporting preliminary data which suggest that the swelling of axons which we produce in rats by iminodipropionitrile, IDPN, is due to its chelating action on copper, and how conversely supplementation with copper abolishes both symptoms and lesions. The copper values we obtained by atomic absorption spectrophotometry of the spinal cord and brain from the animals fully support this contention. In comparing these results with the diseases that are known to be due to copper deficiency, namely Menkes disease in man, swayback in lambs and several neurological mutant mice, we find not only similar axonal swellings, but also amelioration of symptoms and lesions by early administration of copper. Considering the main forms in which copper is present, we discuss the cuproproteins, i.e. ceruloplasmin and metallothionein, and their role in transport and delivery of copper to various organs. Further, the many cuproenzymes i.e. superoxide dismutase, tryptophan-2,3-dioxygenase, lysine oxidase, cytochrome oxidase, monoamine oxidases, tyrosinase, dopamine-beta-hydroxylase and d-amino levulinate dehydratase are noted for their roles in the nervous system. Finally, we suggest that neuronal copper deficiency should be more fully investigated as a possible etiological factor in the more common neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis, ALS.
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PMID:Deficiency of copper can cause neuronal degeneration. 161 61

The effects of copper administration to neonatal male mice on the copper concentrations and activities of copper-containing enzymes in cerebrum, liver, and kidney were studied. Intraperitoneal copper injections at 7 and 10 days of age increased the activities of superoxide dismutase and cytochrome oxidase in cerebrum and liver, and also increased the copper concentrations in cerebrum, liver, and kidney at 13 days of age. Maternal copper administration during the late-gestational period (from 13 days gestation to delivery) decreased the activities of both enzymes and increased the copper concentration in cerebrum. This increased level of copper remained by 13 days of age after birth. Liver showed similar changes to those in cerebrum, but the renal responses were less remarkable. Maternal copper administration from the late-gestational through lactational periods affected neonatal growth, decreased the activity of cytochrome oxidase, and increased the copper concentrations in all tissues examined. It is known that the copper concentration and copper-containing enzyme activity are low in cerebrum of mottled mice as well as of patients with Menkes' disease. These results suggested that the cytochrome oxidase activity in cerebrum was decreased by not only copper deficiency but also excess. The combination of prenatal copper supplementation by means of maternal copper administration during the late-gestational period and intraperitoneal copper injections after birth, while being careful not to overdose, is expected to be efficient for the copper supplementation to mottled mice.
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PMID:Effects of copper administration on fetal and neonatal mice. 324 47

There are several known examples of mutations which influence copper homeostasis in humans and animals. Pleiotropic effects are observed when the mutant gene disturbs copper flux. In some cases, the mutation alters the level of a specific copper ligand (enzyme) and the clinical consequences are unique. The two most widely studied genetic maladies in humans are Menkes' and Wilson's diseases. Menkes' disease is an X-linked fatal disorder in which copper accumulates in some organs (intestine and kidney) and is low in others (liver and brain). Wilson's disease is an autosomal recessive disorder in which copper accumulates, if untreated, in liver and subsequently in brain and kidney. Pathophysiological consequences of copper deficiency and toxicity characterize these two disorders. Specific mutations of human cuproenzymes include overproduction of copper-zinc superoxide dismutase in Down's syndrome, absence of tyrosinase in albinism, hereditary mitochondrial myopathy due to reduction in cytochrome c oxidase, and altered lysyl oxidase in X-linked forms of cutis laxa and Ehlers-Danlos syndrome. Mutations altering copper metabolism are also known in animals. Several murine mutants have been studied. The most extensively investigated mutants are the mottled mice, in particular brindled mice, which have a mutation analogous to that of Menkes' disease. Another recently described murine mutation is toxic milk (tx) an autosomal recessive disorder that is characterized by copper accumulation in liver. Two other mutants, crinkled and quaking, were once thought to exhibit abnormal copper metabolism. Recent data has not confirmed this. A mutation in Bedlington terriers has been described which is very similar to Wilson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Genetic diseases of copper metabolism. 351 56

An animal model for Menkes' kinky hair syndrome is provided by mice mutant at the X-linked mottled locus. Two mechanisms have been invoked to explain disease manifestations in mottled and in kinky hair syndrome: relative tissue copper deficiencies and corresponding reductions in cuproenzyme activities; or defective intracellular copper utilization, with impaired intracellular translocation to cuproenzymes or to copper-dependent processes. We addressed the second possibility through measurements of soluble superoxide dismutase (SOD-1) in cytosol extracts of confluent mottled (blotchy) cultured skin fibroblasts. At comparable intracellular copper concentrations over a broad range, SOD-1 specific activities in the mutant cells were not distinguishable from those in controls, or, in some instances, were actually higher. These data suggest that the excess copper anomalously sequestered in a cell expressing the mutation remains available for binding to a cytosolic cuproenzyme. When taken together with data in other systems, the results are consistent with the thesis that the basic lesion in blotchy may primarily affect copper transport or delivery to specific copper transport systems.
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PMID:Copper utilization in cultured skin fibroblasts of the mottled mouse, an animal model for Menkes' kinky hair syndrome. 644 65

The role of copper in maintaining normal neurological function has been examined in animals copper-deficient by dietary means, and in the genetic disorders of copper homeostasis -- Menkes' kinky-hair disease in humans and the mottled (Mo) mutants in the mouse. With the exception of the disorder in Mo mice, reduced myelination is a constant feature of these copper diseases but there is otherwise a lack of conformity in the structural defects produced in different species. Dietary copper-deficient animals show a reduction in noradrenaline and dopamine concentrations, together with a depressed tyrosine 3-monooxygenase activity (EC 1.14.16.2). Noradrenaline concentrations are also reduced in brain tissue of Mo mice and this reduction is associated with a decrease in the vivo activity of the copper metalloenzyme, dopamine beta-monooxygenase (EC 1.14.17.1). Many tissues contain potent inhibitors of dopamine beta-monooxygenase activity, and assays of this enzyme have utilized cupric ions to inactivate these inhibitors. The elevated in vitro activities of dopamine beta-monooxygenase obtained for both Mo brain and adrenal tissue may therefore reflect either a reduced inactivation of these endogenous inhibitors in the intact animal or the activation in vitro of apoenzyme. Concentrations of dopamine and tyrosine 3-monooxygenase are unchanged in Mo mice. The reduction in dopamine and tyrosine 3-monooxygenase activity in dietary copper-deficient animals may therefore reflect neuronal loss rather than reduced catalytic activity of the catecholamine biosynthetic pathway. The possible effects of depressed activities of cytochrome c oxidase (EC 1.9.3.1) and superoxide dismutase (EC 1.15.1.1) in the development of neurological dysfunction are also discussed, and attention is drawn to the possible significance of the elevated uptake of neutral amino acids, especially tyrosine and tryptophan, by Mo brain tissue.
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PMID:Copper and neurological function. 690 87

Copper is an essential dietary component, being the coenzyme of many enzymes with oxidase activity, e.g. ceruloplasmin, superoxide dismutase, monoamine oxidase, etc. The metabolism of copper is complex and imperfectly known. Active transport of copper through the intestinal epithelial cells involves metallothionein, a protein rich in sulfhydryl groups which also binds the copper in excess and probably prevents absorption in toxic amounts. In hepatocytes a metallothionein facilitates absorption by a similar mechanism and regulates copper distribution in the liver: incorporation in an apoceruloplasmin, storage and synthesis of copper-dependent enzymes. Metallothioneins and ceruloplasmin are essential to adequate copper homeostasis. Apart from genetic disorders, diseases involving copper usually result from hypercupraemia of varied origin. Wilson's disease and Menkes' disease, although clinically and pathogenetically different, are both marked by low ceruloplasmin and copper serum levels. The excessive liver retention of copper in Wilson's disease might be due to increased avidity of hepatic metallothioneins for copper and decreased biliary excretion through lysosomal dysfunction. Menkes' disease might be due to low avidity of intestinal and hepatic metallothioneins for copper. The basic biochemical defect responsible for these two hereditary conditions has not yet been fully elucidated.
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PMID:[Copper pathology (author's transl)]. 705 50

This comparative immunohistochemical study deals with the expression of the cytosolic Cu/Zn-binding and mitochondrial Mn-dependent superoxide dismutases (SODs) in the cerebella of five patients with Menkes' kinky hair disease (MKHD) and five age-matched controls. Several cell types, including Purkinje cells and reactive astrocytes, of all MKHD patients examined were intensely stained by an antibody to Mn SOD, but not by an anti-Cu/Zn SOD antibody. By contrast, the cells of the five controls reacted very weakly or not at all with the anti-Mn SOD antibody, but were strongly reactive with the antibody to Cu/Zn SOD. These results suggest that the increased Mn SOD immunoreactivity in MKHD reflects enzyme induction as a protective mechanism against the highly toxic superoxide anion generated under the disease conditions.
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PMID:Cerebellar superoxide dismutase expression in Menkes' kinky hair disease: an immunohistochemical investigation. 748 97

To elucidate the roles played by copper-containing enzymes in the brain degeneration associated with Menkes disease, the brains of brindled mouse hemizygotes (BMs) were studied histochemically and biochemically before and after copper therapy. Light and electron microscopic histochemistry revealed that, while neuronal mitochondria in BM brains demonstrate only a weak diaminobenzidine reaction for cytochrome oxidase, these exhibit strong activity after therapy and in control mice. Biochemical assays of enzyme activity revealed only 30% of the normal level before a single subcutaneous application of 50 micrograms of CuCl2, whereas neuronal mitochondria of BMs surviving 8 months after the copper therapy displayed essentially no difference from the controls. Similar results were also gained for superoxide dismutase activity, although the reduction was less marked. The present findings provide direct support for decreased activities of copper-containing enzymes being responsible for the mitochondrial abnormalities and brain degeneration associated with Menkes disease.
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PMID:Complete recovery of cytochrome oxidase and superoxide dismutase activities in the brain of brindled mice receiving copper therapy. 812 2

Animal and human studies have shown that copper is involved in the function of several enzymes. Studies have also shown that copper is required for infant growth, host defense mechanisms, bone strength, red and white cell maturation, iron transport, cholesterol and glucose metabolism, myocardial contractility, and brain development. Copper deficiency can result in the expression of an inherited defect such as Menkes syndrome or in an acquired condition. Acquired deficiency is mainly a pathology of infants; however, it has been diagnosed also in children and adults. Most cases of copper deficiency have been described in malnourished children. The most constant clinical manifestations of acquired copper deficiency are anemia, neutropenia, and bone abnormalities. Other, less frequent manifestations are hypopigmentation of the hair, hypotonia, impaired growth, increased incidence of infections, alterations of phagocytic capacity of the neutrophils, abnormalities of cholesterol and glucose metabolism, and cardiovascular alterations. Measurements of serum copper and ceruloplasmin concentrations are currently used to evaluate copper status. These indexes are diminished in severe to moderate copper deficiency; however, they are less sensitive to marginal copper deficiency. Erythrocyte superoxide dismutase and platelet cytochrome c activities may be more promising indexes for evaluating marginal copper deficiency.
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PMID:Copper as an essential nutrient. 861 66

The incorporation of copper into Cu,Zn-superoxide dismutase (SOD) was examined in Menkes lymphoblasts that express a genetic defect of copper metabolism. SOD activity was approximately 40% higher in Menkes than normal lymphoblasts. Since Menkes lymphoblasts contain elevated copper levels, the higher SOD activity is most likely due to near copper saturation of an apoSOD pool that is in normal lymphoblasts. Cycloheximide markedly inhibited 64Cu(II) incorporation into SOD in Menkes lymphoblasts under conditions in which no significant, de novo synthesis of SOD protein was detected with normal lymphoblasts. The maximal amount of 64Cu incorporation into newly synthesized SOD in Menkes lymphoblasts was approximately equal to the maximal amount of 64Cu that could be incorporated into the apoSOD pool in normal lymphoblasts. The increased synthesis of SOD in Menkes lymphoblasts may play a protective role against copper toxicity in Menkes lymphoblasts. The protonophore, CCCP markedly inhibited 64Cu incorporation into SOD in both normal and Menkes lymphoblasts, which is consistent with 64Cu incorporation into SOD within a membrane-bounded compartment in both cell types. When 64Cu-incorporation into SOD was blocked with CCCP, copper accumulated in a Superose column fraction that contains S-adenosylhomocysteine hydrolase (SAHH), which has a high affinity for copper. SAHH may play a role in delivering copper to SOD.
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PMID:Copper incorporation into superoxide dismutase in Menkes lymphoblasts. 891 Apr 56


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