Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sections of the spinal cord from 10 patients with classic amyotrophic lateral sclerosis and from 10 control cases were examined by immunocytochemical methods to localize metallothionein. Metallothionein immunoreactivity was seen in the nucleus and cytoplasm of a subset of astrocytes, largely confined to the gray matter. Also, diffuse gray matter staining was observed, probably representing small glial fibers. Astrocytic metallothionein immunoreactivity (P less than 0.01) and strong gray matter matrix staining (P less than 0.03) was increased in the spinal cords from patients with amyotrophic lateral sclerosis. Although compatible with induction by metals, increased metallothionein expression in the spinal cords from patients with amyotrophic lateral sclerosis may also have resulted from inflammation or gliosis.
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PMID:Metallothionein immunoreactivity is increased in the spinal cord of patients with amyotrophic lateral sclerosis. 143 88

To evaluate the putative role of metals and trace elements in the pathogenesis of classic amyotrophic lateral sclerosis, we studied the metallothionein levels in liver and kidney samples obtained at autopsy from 24 patients with amyotrophic lateral sclerosis and 18 controls. To assay metallothioneins and copper, cadmium, and zinc bound to metallothioneins, we used high-performance liquid chromatography directly coupled to flame atomic absorption spectrometry. Total cadmium, zinc, and copper concentrations were determined separately with the use of graphite furnace atomic absorption spectrometry with Zeeman background correction. The median liver metallothionein level was 60.3 mg/kg (range, 9 to 318 mg/kg) in the patients with amyotrophic lateral sclerosis and 12.6 mg/kg (range, 0 to 104.5 mg/kg) in the controls. In the kidney, median metallothionein levels were 126.9 mg/kg (range, 44 to 387 mg/kg) in the patients with amyotrophic lateral sclerosis and 64 mg/kg (range, 13.1 to 187 mg/kg) in the controls. Total zinc, cadmium, and copper concentrations, as measured by atomic absorption spectrometry, were not significantly different in patients vs controls. Our finding of elevated metallothionein levels in organs from patients with amyotrophic lateral sclerosis may indicate an increased exposure to metals.
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PMID:Increased metallothionein in the liver and kidney of patients with amyotrophic lateral sclerosis. 149 98

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

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neurons in the spinal cord, brainstem and motor cortex. Ten percent of the cases are familial and these have been linked to point mutations in the gene coding for cytosolic copper, zinc superoxide dismutase. The etiology of sporadic ALS is unknown. To further investigate the possible role of metals in causing the disease, we investigated metallothionein (MT) levels in ALS organs and serum. We previously reported significantly increased MT levels in ALS liver and kidney. These are not reflected in serum MT levels, which are normal in ALS. In ALS spinal cord, MT is expressed in gray matter protoplasmic astrocytes. Induction of MT synthesis in ALS may denote increased metal exposure or may result from increased oxidative stress, as in familial ALS.
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PMID:Metallothionein in amyotrophic lateral sclerosis. 783 14

Growth-inhibitory factor (GIF), which is deficient in the Alzheimer's disease brain, is a 68-amino-acid metallothionein-like protein. GIF is expressed in the central nervous system but not in peripheral tissues including dorsal root ganglion. GIF is immunocytochemically distributed in Bergmann's glia in the cerebellum and astrocytes in the neocortex, hippocampus, striatum, brain stem, and spinal cord. Strong GIF immunoreactivity is localized in astrocyte cell bodies and fine long processes, which are closely associated with neural perikarya and dendrites, such as layers 2-6 of cerebral gray matter, the molecular layer of the dentate gyrus, the pyramidal layer of the hippocampus and spinal gray matter. GIF is induced in reactive astrocytes in the cerebral cortex in cases of meningitis and Creutzfeldt-Jakob disease or in reactive astrocytes surrounding old cerebral infarcts. On the other hand, GIF is reduced in the subset of reactive astrocytes in lesioned areas of degenerative diseases such as Alzheimer's disease, multiple-system atrophy, Parkinson's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis. Reduction of GIF is correlated with neuronal loss. Thus, perturbation in normal neuroglial interaction in degenerative diseases may lead to a reduction of GIF in reactive astrocytes.
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PMID:Growth-inhibitory factor, metallothionein-like protein, and neurodegenerative diseases. 783 16

To clarify the pathological characteristics of astrocytic hyaline inclusions (Ast-HIs) in patients with familial amyotrophic lateral sclerosis (FALS) with neuronal Lewy-body-like hyaline inclusions (LBHIs), eight autopsies on members of four different families, including two long-term surviving patients with clinical courses of over 10 years, were analyzed. Ast-HIs were found only in the two long-term surviving patients who belonged to different families and to different races. Ast-HIs were ultrastructurally composed of 15- to 25-nm granule-coated fibrils that had immunoreactivities to superoxide dismutase 1 (SOD1) and ubiquitin. Approximately 50% of the Ast-HIs expressed alpha B-crystallin, metallothionein, glutamine synthetase, and tubulin (alpha and beta) at various intensities. Some Ast-HIs reacted with antibodies to tau protein, S-100 protein, and heat shock protein 27. The Ast-HIs were not stained for glial fibrillary acidic protein. Our results suggest a cooperative role of superoxide dismutase 1, ubiquitin, and cytoskeletal proteins in the formation of granule-coated fibrils (namely, Ast-HIs) and provide evidence that Ast-HIs are formed in certain long-surviving familial amyotrophic lateral sclerosis patients with neuronal Lewy-body-like hyaline inclusions.
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PMID:Pathological characterization of astrocytic hyaline inclusions in familial amyotrophic lateral sclerosis. 927 21

Zinc is an important trace element in biology. An important pool of zinc in the brain is the one present in synaptic vesicles in a subgroup of glutamatergic neurons. In this form it can be released by electrical stimulation and may serve to modulate responses at receptors for a number of different neurotransmitters. These include both excitatory and inhibitory receptors, particularly the NMDA and GABA(A) receptors. This pool of zinc is the only form of zinc readily stained histochemically (the chelatable zinc pool), but constitutes only about 8% of the total zinc content in the brain. The remainder of the zinc is more or less tightly bound to proteins where it acts either as a component of the catalytic site of enzymes or in a structural capacity. The metabolism of zinc in the brain is regulated by a number of transport proteins, some of which have been recently characterized by gene cloning techniques. The intracellular concentration may be mediated both by efflux from the cell by the zinc transporter ZrT1 and by complexing with apothionein to form metallothlonein. Metallothionein may serve as the source of zinc for incorporation into proteins, including a number of DNA transcription factors. However, zinc is readily released from metallothionein by disulfides, increasing concentrations of which are formed under oxidative stress. Metallothionein is a very good scavenger of free radicals, and zinc itself can also reduce oxidative stress by binding to thiol groups, decreasing their oxidation. Zinc is also a very potent inhibitor of nitric oxide synthase. Increased levels of chelatable zinc have been shown to be present in cell cultures of immune cells undergoing apoptosis. This is very reminiscent of the zinc staining of neuronal perikarya dying after an episode of ischemia or seizure activity. Thus a possible role of zinc in causing neuronal death in the brain needs to be fully investigated. intraventricular injections of calcium EDTA have already been shown to reduce neuronal death after a period of ischemia. Pharmacological doses of zinc cause neuronal death, and some estimates indicate that extracellular concentrations of zinc could reach neurotoxic levels under pathological conditions. Zinc is released in high concentrations from the hippocampus during seizures. Unfortunately, there are contrasting observations as to whether this zinc serves to potentiate or decrease seizure activity. Zinc may have an additional role in causing death in at least some neurons damaged by seizure activity and be involved in the sprouting phenomenon which may give rise to recurrent seizure propagation in the hippocampus. In Alzheimer's disease, zinc has been shown to aggregate beta-amyloid, a form which is potentially neurotoxic. The zinc-dependent transcription factors NF-kappa B and Sp1 bind to the promoter region of the amyloid precursor protein (APP) gene. Zinc also inhibits enzymes which degrade APP to nonamyloidogenic peptides and which degrade the soluble form of beta-amyloid. The changes in zinc metabolism which occur during oxidative stress may be important in neurological diseases where oxidative stress is implicated, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Zinc is a structural component of superoxide dismutase 1, mutations in which give rise to one form of familiar ALS. After HIV infection, zinc deficiency is found which may be secondary to immune-induced cytokine synthesis. Zinc is involved in the replication of the HIV virus at a number of sites. These observations should stimulate further research into the role of zinc in neuropathology.
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PMID:Zinc metabolism in the brain: relevance to human neurodegenerative disorders. 936 Dec 93

Genetic transfer approaches have received recent consideration as potential treatment modalities for human central and peripheral nervous system (CNS and PNS, respectively) neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Transplantation of genetically modified cells into the brain represents a promising strategy for the delivery and expression of specific neurotrophic factors, neurotransmitter-synthesizing enzymes, and cellular regulatory proteins for intervention in neurodegenerative diseases. The use of specific regulatable promoters may also provide potential control of gene expression required for dose-specific or time-specific therapeutic strategies. In this article, we review the potential use of activated promoters in ex vivo systems for the potential genetic therapy of neurodegenerative disorders, and then describe our own studies using the zinc-inducible metallothionein promoter for the regulated expression of nerve growth factor (NGF) in rodent brain transplants.
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PMID:Promoter-activated expression of nerve growth factor for treatment of neurodegenerative diseases. 1051 13

Missense mutations in the gene encoding copper zinc superoxide dismutase (SOD1) have been found to cause one form of familial amyotrophic lateral sclerosis (FALS). Although the exact mechanism of disease is unknown, abnormalities in the ability of mutant SOD1 to bind zinc or copper ions may be crucial in the pathogenesis of disease. Because members of the metallothionein (MT) family of zinc and copper binding proteins function as important cellular regulators of metal ion bioavailability in the central nervous system, we used in situ hybridization and immunohistochemistry to study the expression pattern of these molecules in a transgenic mouse model of familial ALS. In adult wild-type mouse spinal cord, expression of MT-I and MT-II is restricted to ependymal cells and a subset of astrocytes located in white matter tracts, while MT-III synthesis is limited to neurons within gray matter. Compared to wild-type littermates, transgenic mice carrying the G93A SOD1 mutation demonstrate markedly increased expression of MT-I and MT-II within astrocytes in both white and gray matter as weakness develops. MT-III synthesis in neurons is also greatly upregulated as G93A SOD1 animals age, with glial cell expression of MT-III evident by later stages of the disease. Changes in MT expression occur before the onset of motor deficits or significant motor neuron pathology in G93A SOD1 mice and remarkably extend beyond ventral horn populations of neurons and glia. These results are consistent with the hypothesis that metallothioneins may serve an early and important protective function in FALS.
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PMID:Metallothionein expression is altered in a transgenic murine model of familial amyotrophic lateral sclerosis. 1071 86

Mutations of copper,zinc-superoxide dismutase (cu,zn SOD) are found in patients with a familial form of amyotrophic lateral sclerosis. When expressed in transgenic mice, mutant human cu,zn SOD causes progressive loss of motor neurons with consequent paralysis and death. Expression profiling of gene expression in SOD1-G93A transgenic mouse spinal cords indicates extensive glial activation coincident with the onset of paralysis at 3 months of age. This is followed by activation of genes involved in metal ion regulation (metallothionein-I, metallothionein-III, ferritin-H, and ferritin-L) at 4 months of age just prior to end-stage disease, perhaps as an adaptive response to the mitochondrial destruction caused by the mutant protein. Induction of ferritin-H and -L gene expression may also limit iron catalyzed hydroxyl radical formation and consequent oxidative damage to lipids, proteins, and nucleic acids. Thus, glial activation and adaptive responses to metal ion dysregulation are features of disease in this transgenic model of familial amyotrophic lateral sclerosis.
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PMID:Disease mechanisms revealed by transcription profiling in SOD1-G93A transgenic mouse spinal cord. 1176 70


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