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)

Spinal cords of sporadic cases with amyotrophic lateral sclerosis (ALS) and normal controls were immunohistochemically examined using antibodies for nitrotyrosine (NT), Cu/Zn superoxide dismutase (SOD), and nitric oxide synthase (NOS) of brain, endothelial, and inducible forms. Immunoreactivity for NT was densely detected in the motor neurons of ALS while it was not or was only minimally detected in those of controls. The staining was also found in the axons of motor neurons of ALS, but was not found in the controls. In contrast, although immunoreactivity for Cu/Zn SOD of the motor neurons was dense in the motor neurons, it was not different between the ALS and controls. Immunoreactivities for bNOS and eNOS in the motor neurons of ALS were stronger than those of controls, and were also found in degenerated axons in the anterior horn of ALS. However, the immunoreactivity for inducible NOS was only minimally detected in the motor neurons of ALS and controls, and was not detected in the degenerated axons of ALS. These results suggest that nitration of protein-tyrosine residue is upregulated in motor neurons of the spinal cord of ALS with selective increases of brain NOS- and endothelial NOS-like immunoreactivities.
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PMID:Upregulation of protein-tyrosine nitration in the anterior horn cells of amyotrophic lateral sclerosis. 917 39

Clinical and molecular analyses of neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 1 (SCA1) were performed. In the present study, a Japanese family of AD with an Ala285Val substitution in exon 8 of the presenilin-1 (PS-1) gene was found. This family was characterized by relatively late onset (mean age at 50 years) in familial AD with PS-1 gene mutation and by absence of myoclonus, seizure or paratonia. Magnetic resonance image (MRI) study showed marked linear signal abnormalities in white matter of parietoocctipital lobes, suggesting a presence of cortical amyloid angiopathy of the patient with PS-1 gene mutation. Clinical characteristics of familial amyotrophic lateral sclerosis (FALS) with four different missense point mutations in exons 2, 4, and 5 of the Cu/Zn superoxide dismutase (SOD) gene were reported. Although features of progressive neurogenic muscular atrophy was common in patients of these families, patients of each family showed characteristic clinical features. Although lower motor sign was evident in all cases, hyperreflexia varied from 0 to 100% among patients with the different mutations, and Babinski sign was not observed in any cases. Bulbar palsy was frequent with a mutation, but not present with another mutation. SOD activity of red blood cells was generally reduced with minor variations. CAG trinucleotide repeat expansion was analyzed in 25 families with hereditary ataxia of Menzel type in the northeast of Japan. Twenty of 38 patients in 12 families had expanded allele for spinocerebellar ataxia type 1 (SCA1). Study of the number of CAG repeats in various tissues showed no differences in the repeat length in lymphocytes, muscle or brain; sperm, however, showed an obvious expansion. This may be a clue to a possible mechanism for the molecular basis of paternal anticipation of the disease. These results suggest that clinical features of some familial cases of neurodegenerative diseases such as AD, ALS, and SCA1 are well correlated with their genetic mutations.
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PMID:Clinical and molecular analysis of neurodegenerative diseases. 921 Feb 48

A subpopulation of familial cases of amyotrophic lateral sclerosis has been linked to mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). There is in vitro evidence that certain SOD1 mutants, in addition to their normal dismutation function, show increased ability of the enzyme to act as a peroxidase. This reaction is sensitive to inhibition by copper chelators. To test this hypothesis in vivo, we administered the copper chelator d-penicillamine to a transgenic mouse model of familial amyotrophic lateral sclerosis overexpressing a mutated form of human SOD1. We demonstrate that oral administration of d-penicillamine is able to delay the onset of the disease and extend the survival of these mice. Histological studies also showed a decreased loss of facial motor neurons in d-penicillamine-treated transgenic mice, corroborating the slower evolution of the disease in these animals. These results suggest that copper chelators may benefit patients with familial amyotrophic lateral sclerosis linked to mutations in the SOD1 gene.
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PMID:The copper chelator d-penicillamine delays onset of disease and extends survival in a transgenic mouse model of familial amyotrophic lateral sclerosis. 924 Apr 14

Rosen et al. have reported point mutations in the cytosolic Cu/Zn superoxide dismutase (SOD 1) gene in some families with familial amyotrophic lateral sclerosis (ALS). To determine whether decreased SOD activity could contribute to neuronal damage, rat embryo ventral spinal cord neurons were incubated with diethyldithiocarbamate (DDC), an inhibitor of SOD. There was a marked increase in neuronal damage in cultures exposed to DDC and this phenomenon was dose-related. In this paradigm, these deteriorative changes were prevented by bromocriptine. DDC-treated ventral spinal cord neurons provide an in vitro model of free radical neurotoxicity secondary to decreased SOD activity. Simultaneous treatment with bromocriptine and DDC reduced neurotoxicity, indicating that bromocriptine has a neuroprotective effect against free radicals.
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PMID:Bromocriptine prevents neuron damage following inhibition of superoxide dismutase in cultured ventral spinal cord neurons. 926 19

Apoptotic, rather than necrotic, nerve cell death now appears as likely to underlie a number of common neurological conditions including stroke, Alzheimer's disease, Parkinson's disease, hereditary retinal dystrophies and Amyotrophic Lateral Sclerosis. Apoptotic neuronal death is a delayed, multistep process and therefore offers a therapeutic opportunity if one or more of these steps can be interrupted or reversed. Research is beginning to show how specific macromolecules play a role in determining the apoptotic death process. We are particularly interested in the critical nature of gradual mitochondrial failure in the apoptotic process and propose that a maintenance of mitochondrial function through the pharmacological modulation of gene expression offers an opportunity for the effective treatment of some types of neurological dysfunction. Our research into the development of small diffusible molecules that reduce apoptosis has grown from studies of the irreversible MAO-B inhibitor (-)-deprenyl. (-)-Deprenyl can reduce neuronal death independently of MAO-B inhibition even after neurons have sustained seemingly lethal damage. (-)-Deprenyl can also influence the process outgrowth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with earlier work of others, we showed that (-)-deprenyl alters the expression of a number of mRNAs or of proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD-2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial membrane potential correlates with mitochondrial ATP production, we have used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl result in a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and decrease cytoplasmic oxidative radical levels and thereby reduces apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may lead to the development of new therapies for neurodegenerative diseases.
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PMID:Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription. 926 33

Mutations in human Cu/Zn superoxide dismutase-1 (SOD) cause approximately 20% of cases of familial amyotrophic lateral sclerosis (FALS). We investigated the mechanism of mutant SOD-induced neuronal degeneration by expressing wild-type and mutant SODs in neuronal cells by means of infection with replication-deficient recombinant adenoviruses. Expression of two FALS-related mutant SODs (A4V and V148G) caused death of differentiated PC12 cells, superior cervical ganglion neurons, and hippocampal pyramidal neurons. Cell death included many features typical of apoptosis. Death could be prevented by copper (Cu2+) chelators, Bcl-2, glutathione, vitamin E, and inhibitors of caspases. Mutant SOD-expressing PC12 cells had higher rates of superoxide (O2-) production under a variety of conditions. The results support the hypothesis that mutant SOD induced-neurodegeneration is associated with disturbances of neuronal free radical homeostasis.
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PMID:Mutant superoxide dismutase-1-linked familial amyotrophic lateral sclerosis: molecular mechanisms of neuronal death and protection. 934 45

Mutations to Cu/Zn superoxide dismutase (SOD) linked to familial amyotrophic lateral sclerosis (ALS) enhance an unknown toxic reaction that leads to the selective degeneration of motor neurons. However, the question of how >50 different missense mutations produce a common toxic phenotype remains perplexing. We found that the zinc affinity of four ALS-associated SOD mutants was decreased up to 30-fold compared to wild-type SOD but that both mutants and wild-type SOD retained copper with similar affinity. Neurofilament-L (NF-L), one of the most abundant proteins in motor neurons, bound multiple zinc atoms with sufficient affinity to potentially remove zinc from both wild-type and mutant SOD while having a lower affinity for copper. The loss of zinc from wild-type SOD approximately doubled its efficiency for catalyzing peroxynitrite-mediated tyrosine nitration, suggesting that one gained function by SOD in ALS may be an indirect consequence of zinc loss. Nitration of protein-bound tyrosines is a permanent modification that can adversely affect protein function. Thus, the toxicity of ALS-associated SOD mutants may be related to enhanced catalysis of protein nitration subsequent to zinc loss. By acting as a high-capacity zinc sink, NF-L could foster the formation of zinc-deficient SOD within motor neurons.
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PMID:Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite. 934 38

Some cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), suggesting that oxidative damage may play a role in ALS pathogenesis. To further investigate the biochemical features of FALS and sporadic ALS (SALS), we examined markers of oxidative damage to protein, lipids, and DNA in motor cortex (Brodmann area 4), parietal cortex (Brodmann area 40), and cerebellum from control subjects, FALS patients with and without known SOD mutations, SALS patients, and disease controls (Pick's disease, progressive supranuclear palsy, diffuse Lewy body disease). Protein carbonyl and nuclear DNA 8-hydroxy-2'-deoxyguanosine (OH8dG) levels were increased in SALS motor cortex but not in FALS patients. Malondialdehyde levels showed no significant changes. Immunohistochemical studies showed increased neuronal staining for hemeoxygenase-1, malondialdehyde-modified protein, and OH8dG in both SALS and FALS spinal cord. These studies therefore provide further evidence that oxidative damage may play a role in the pathogenesis of neuronal degeneration in both SALS and FALS.
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PMID:Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. 934 52

Mice engineered to express a transgene encoding a human Cu/Zn superoxide dismutase (SOD1) with a Gly93 --> Ala (G93A) mutation found in patients who succumb to familial amyotrophic lateral sclerosis (FALS) develop a rapidly progressive and fatal motor neuron disease (MND) similar to amyotrophic lateral sclerosis (ALS). Hallmark ALS lesions such as fragmentation of the Golgi apparatus and neurofilament (NF)-rich inclusions in surviving spinal cord motor neurons as well as the selective degeneration of this population of neurons were also observed in these animals. Since the mechanism whereby mutations in SOD1 lead to MND remains enigmatic, we asked whether NF inclusions in motor neurons compromise axonal transport during the onset and progression of MND in a line of mice that contained approximately 30% fewer copies of the transgene than the original G93A (Gurney et al., 1994). The onset of MND was delayed in these mice compared to the original G93A mice, but they developed the same neuropathologic abnormalities seen in the original G93A mice, albeit at a later time point with fewer vacuoles and more NF inclusions. Quantitative Western blot analyses showed a progressive decrease in the level of NF proteins in the L5 ventral roots of G93A mice and a concomitant reduction in axon caliber with the onset of motor weakness. By approximately 200 d, both fast and slow axonal transports were impaired in the ventral roots of these mice coincidental with the appearance of NF inclusions and vacuoles in the axons and perikarya of vulnerable motor neurons. This is the first demonstration of impaired axonal transport in a mouse model of ALS, and we infer that similar impairments occur in authentic ALS. Based on the temporal correlation of these impairments with the onset of motor weakness and the appearance of NF inclusions and vacuoles in vulnerable motor neurons, the latter lesions may be the proximal cause of motor neuron dysfunction and degeneration in the G93A mice and in FALS patients with SOD1 mutations.
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PMID:Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. 938 75

We report the clinical, genetic, and neuropathologic findings in a patient with rapidly progressive familial amyotrophic lateral sclerosis (ALS). We detected a point mutation at codon 48 of the Cu/Zn superoxide dismutase gene (SOD1) leading to a substitution of histidine by glutamine in the copper-binding domain. The histopathologic features are consistent with those described in rapidly progressive sporadic ALS and do not support claims that sporadic and familial disease are different pathologic entities. Neurofilamentous accumulations, hyaline, and ubiquitinated inclusions were present in the motor cortex, brainstem, and anterior horn cells, but there was no evidence of abnormal SOD1 immunoreactivity. This confirms that the cytoskeletal pathology specific to ALS is secondary to an unknown biochemical disturbance caused by mutant SOD1 molecules and not its toxic accumulation.
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PMID:Familial amyotrophic lateral sclerosis. Molecular pathology of a patient with a SOD1 mutation. 940 55


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