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)

Treatment of amyotrophic lateral sclerosis (ALS) with anti-glutamate agents has had some success, but the search continues for more effective glutamate blockers. Magnesium (Mg) ions inhibit the opening of some glutamate receptors, so we increased dietary Mg in a mouse model of ALS in an attempt to modify the course of the disease. From the age of 6 weeks, mutant superoxide dismutase 1 (SOD1) transgenic mice and wild-type controls had either 0, 21.5 or 43 g/l of Mg pidolate added to their drinking water. Disease onset was measured by tests for coordination and forelimb strength, and survival by standard endpoints. Mg levels in the brain were measured in wild-type mice using mass spectrometry. Mutant SOD1 mice on no added Mg became weak at about 105 days, and survived between 114 and 137 days. No difference in either time of onset of weakness, or survival, was seen in mutant SOD1 mice on different doses of Mg. No increase in wild-type brain Mg was found after supplemental Mg. From these results, it appears that a trial of oral Mg supplementation in human ALS is not warranted.
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PMID:Magnesium supplementation does not delay disease onset or increase survival in a mouse model of familial ALS. 1460 8

Living cells produce reactive oxygen species (ROSs). To protect themselves from these ROSs, the cells have developed both an antioxidant system containing superoxide dismutase 1 (SOD1) and a redox system including peroxiredoxin2 (Prx2, thioredoxin peroxidase) and glutathione peroxidase1 (GPx1): SOD1 converts superoxide radicals into hydrogen peroxide (H2O2), and H2O2 is then converted into harmless water (H2O) and oxygen (O2) by Prx2 and GPx1 that directly regulate the redox system. To clarify the biological significance of the interaction of the redox system (Prx2/GPx1) with SOD1 in SOD1-mutated motor neurons in vivo, we produced an affinity-purified rabbit antibody against Prx2 and investigated the immunohistochemical localization of Prx2 and GPx1 in neuronal Lewy body-like hyaline inclusions (LBHIs) in the spinal cords of familial amyotrophic lateral sclerosis (FALS) patients with a two-base pair deletion at codon 126 and an Ala-->Val substitution at codon 4 in the SOD1 gene, as well as in transgenic rats expressing human SOD1 with H46R and G93A mutations. The LBHIs in motor neurons from the SOD1-mutated FALS patients and transgenic rats showed identical immunoreactivities for Prx2 and GPx1: the reaction product deposits with the antibodies against Prx2 and GPx1 were localized in the LBHIs. In addition, the localizations of the immunoreactivities for SOD1 and Prx2/GPx1 were similar in the inclusions: the co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs in mutant SOD1-related FALS patients and transgenic rats was evident. Based on the fact that Prx2/GPx1 directly regulates the redox system, such co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs may lead to the breakdown of the redox system itself, thereby amplifying the mutant SOD1-mediated toxicity in mutant SOD1-linked FALS patients and transgenic rats expressing human mutant SOD1.
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PMID:Histological evidence of redox system breakdown caused by superoxide dismutase 1 (SOD1) aggregation is common to SOD1-mutated motor neurons in humans and animal models. 1464 77

It is estimated that between 10-20% of amyotrophic lateral sclerosis (ALS) is familial and these cases encompass recessive and dominant modes of inheritance. So far, mutations in three genes, superoxide dismutase 1 (SOD1), the p150 subunit of dynactin (DCTN1), and alsin have been shown to be directly causal for motor neuron degeneration in humans. However, clearly the disorder is genetically heterogeneous and other causal genes remain to be found that explain the vast majority of familial ALS cases. Human genetics can be problematical in that it is difficult to detect linkage in disorders in which multiple loci give similar phenotypes and where families are often small. In addition, the vertical collection of generations is often not possible with late onset disorders. An excellent genetic model of humans is provided by the mouse. We can use mouse models of neurodegeneration to find new genes in the human population. These models are not exact replicas of the human condition, but are the mouse equivalent and are incredibly valuable resources for highlighting genes and biochemical pathways disrupted in ALS and other diseases. In addition mouse models give us access to both control and affected tissues, at all stages of development and disease, thus greatly facilitating our understanding of pathogenesis. They also provide us with model systems for testing new therapies. Here we describe the approach taken to the characterization of new models of motor neuron disease and illustrate this with examples, including a recently characterized mouse model, Legs at odd angles (Loa).
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PMID:Paradigms for the identification of new genes in motor neuron degeneration. 1475 59

Innate immunity is a specific and organized immunological program engaged by peripheral organs and the CNS to maintain homeostasis after stress and injury. In neurodegenerative disorders, its putative deregulation, featured by inflammation and activation of glial cells resulting from inherited mutations or viral/bacterial infections, likely contributes to neuronal death. However, it remains unclear to what extent environmental factors and innate immunity cooperate to modulate the interactions between the neuronal and non-neuronal elements in the perturbed CNS. In the present study, we addressed the effects of acute and chronic administration of lipopolysaccharide (LPS), a Gram-negative bacterial wall component, in a genetic model of neurodegeneration. Transgenic mice expressing a mutant form of the superoxide dismutase 1 (SOD1(G37R)) linked to familial amyotrophic lateral sclerosis were challenged intraperitoneally with a single nontoxic or repeated injections of LPS (1 mg/kg). At different ages, SOD1(G37R) mice responded normally to acute endotoxemia. Remarkably, only a chronic challenge with LPS in presymptomatic 6-month-old SOD1(G37R) mice exacerbated disease progression by 3 weeks and motor axon degeneration. Closely associated with the severity of disease is the stronger and restricted upregulation of the receptor of innate immunity Toll-like receptor 2 and proinflammatory cytokines in degenerating regions of the ventral spinal cord and efferent fiber tracts of the brain from the LPS-treated SOD1(G37R) mice. This robust immune response was not accompanied by the establishment of acquired immunity. Our results provide solid evidence that environmental factors and innate immunity can cooperate to influence the course of disease of an inherited neuropathology.
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PMID:Exacerbation of motor neuron disease by chronic stimulation of innate immunity in a mouse model of amyotrophic lateral sclerosis. 1496 Jun 5

About 20 p. cent of cases of amyotrophic lateral sclerosis are familial (FALS). Fifteen percent of FALS cases are associated with an abnormality in the superoxide dismutase 1 (SOD1) gene. To date, more than 100 different genetic abnormalities have been reported, all except two are autosomal dominant. The clinical characteristics of patients presenting with FALS associated with an SOD1 abnormality is homogeneous when there is no doubt about the hereditary aspect of the genetic abnormality: mean age at onset 42 years, limb onset, slow evolution. Except when present in the setting of a clearly inherited disease (FALS) (several patients through several generations), the causality of a given SOD1 mutation often remains an open question. Consequently, search for SOD1 mutation is not warranted when atypical features such as young age at onset or slow progression are present. Conversely, a complete family study is justified to determine the precise role of a given SOD1 mutation because of the large number of potential SOD1 mutations, the variability of the transmission mode, and the non-exceptional absence of proven causality for ALS. Specific cases where a frequent SOD1 mutation with a recognized causal effect is recognized (no more than 15 out of more than 90 mutations) would be an exception.
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PMID:[Superoxyde dismutase 1 gene abnormalities in familial amyotrophic lateral sclerosis: phenotype/genotype correlations. The French experience and review of the literature]. 1497 93

MRI has been used to measure hindlimb muscle volume in female and male transgenic mice overexpressing the Gly93Ala (G93A) mutant human superoxide dismutase 1 (SOD1), a widely used model of familial amyotrophic lateral sclerosis (FALS), over the first 4 months of life. Significant decreases in the hindlimb muscle volume of the female G93A SOD1 mice were evident from 11 weeks of age, before other overt pathology appeared. By 15 weeks volume had decreased by 37% compared with 7 weeks, from 0.84+/-0.04 cm(3) (mean+/-standard deviation, n = 6) to 0.54+/-0.07 cm(3), (p < 0.05), despite an increase in body weight of ca. 12% (from 16.2 +/- 1.4 to 18.1 +/- 0.7 g). Female wild-type volume increased by ca. 30% whilst the body weight increased by 15%. Muscle wasteage was less (0.82+/-0.1 to 0.65+/-0.02 cm(3), p < 0.05, n = 6) in male G93A SOD1 mice between 8 and 16 weeks of age, against a body weight increase trend from 20.7 +/- 0.4 to 21.6 +/- 0.5 g, (p > 0.05). Wild-type male muscle volume did not change significantly over this period, with an increase in body weight of 20%. Longitudinal MRI hindlimb muscle volume measurements may provide a straightforward, rapid, non-invasive and sensitive, way of monitoring outcome of experimental ALS treatments.
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PMID:MRI detects early hindlimb muscle atrophy in Gly93Ala superoxide dismutase-1 (G93A SOD1) transgenic mice, an animal model of familial amyotrophic lateral sclerosis. 1501 Dec 48

Abstract Dorfin is a RING-finger type ubiquitin ligase for mutant superoxide dismutase 1 (SOD1) that enhances its degradation. Mutant SOD1s cause familial amyotrophic lateral sclerosis (FALS) through the gain of unelucidated toxic properties. We previously showed that the accumulation of mutant SOD1 in the mitochondria triggered the release of cytochrome c, followed by the activation of the caspase cascade and induction of neuronal cell death. In the present study, therefore, we investigated whether Dorfin can modulate the level of mutant SOD1 in the mitochondria and subsequent caspase activation. We showed that Dorfin significantly reduced the amount of mutant SOD1 in the mitochondria, the release of cytochrome c and the activation of the following caspase cascade, thereby preventing eventual neuronal cell death in a neuronal cell model of FALS. These results suggest that reducing the accumulation of mutant SOD1 in the mitochondria may be a new therapeutic strategy for mutant SOD1-associated FALS, and that Dorfin may play a significant role in this.
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PMID:Dorfin prevents cell death by reducing mitochondrial localizing mutant superoxide dismutase 1 in a neuronal cell model of familial amyotrophic lateral sclerosis. 1503 Mar 90

High molecular weight detergent-insoluble complexes of superoxide dismutase 1 (SOD1) enzyme are a biochemical abnormality associated with mutant SOD1-linked familial amyotrophic lateral sclerosis (FALS). In the present study, SOD1 protein from spinal cords of transgenic FALS mice was fractionated according to solubility in saline, zwitterionic, non-ionic or anionic detergents. Both endogenous mouse SOD1 and mutant human SOD1 were least soluble in SDS, followed by NP-40 and CHAPS, with an eight-fold greater detergent resistance of mutant protein overall. Importantly, high molecular weight mutant SOD1 complexes were isolated with SDS-extraction only. To reproduce SOD1 aggregate pathology in vitro, primary fibroblasts were isolated and cultured from neonatal transgenic FALS mice. Fibroblasts expressed abundant mutant SOD1 without spontaneous aggregation over time with passage. Proteasomal inhibition of cultures using lactacystin induced dose-dependent aggregation and increased the SDS-insoluble fraction of mutant SOD1, but not endogenous SOD1. In contrast, paraquat-mediated superoxide stress in fibroblasts promoted aggregation of endogenous SOD1, but not mutant SOD1. Treatment of cultures with peroxynitrite or the copper chelator diethyldithiocarbamate (DDC) alone did not modulate aggregation. However, DDC inhibited lactacystin-induced mutant SOD1 aggregation in transgenic fibroblasts, while exogenous copper slightly augmented aggregation. These data suggest that SOD1 aggregates may derive from proteasomal or oxidation-mediated oligomerisation pathways from mutant and endogenous subunits respectively. Furthermore, these pathways may be affected by copper availability. We propose that non-neural cultures such as these transgenic fibroblasts with inducible SOD1 aggregation may be useful for rapid screening of compounds with anti-aggregation potential in FALS.
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PMID:Inducible superoxide dismutase 1 aggregation in transgenic amyotrophic lateral sclerosis mouse fibroblasts. 1503 41

The Cu- and Zn-containing superoxide dismutase 1 (SOD1) largely obtains Cu in vivo by means of the action of the Cu chaperone CCS. Yet, in the case of mammalian SOD1, a secondary pathway of activation is apparent. Specifically, when human SOD1 is expressed in either yeast or mammalian cells that are null for CCS, the SOD1 enzyme retains a certain degree of activity. This CCS-independent activity is evident with both wild-type and mutant variants of SOD1 that have been associated with familial amyotrophic lateral sclerosis. We demonstrate here that the CCS-independent activation of mammalian SOD1 involves glutathione, particularly the reduced form, or GSH. A role for glutathione in CCS-independent activation was seen with human SOD1 molecules that were expressed in either yeast cells or immortalized fibroblasts. Compared with mammalian SOD1, the Saccharomyces cerevisiae enzyme cannot obtain Cu without CCS in vivo, and this total dependence on CCS involves the presence of dual prolines near the C terminus of the SOD1 polypeptide. Indeed, the insertion of such prolines into human SOD1 rendered this molecule refractory to CCS-independent activation. The possible implications of multiple pathways for SOD1 activation are discussed in the context of SOD1 evolutionary biology and familial amyotrophic lateral sclerosis.
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PMID:Mechanisms for activating Cu- and Zn-containing superoxide dismutase in the absence of the CCS Cu chaperone. 1506 87

An Italian collaborative group on motor neuron disorders, including amyotrophic lateral sclerosis (ALS) and its variants, has been recently created, combining various academic groups and laboratories involved in basic and clinical research. The aim is to exploit all the specific expertise and combine efforts at a national level to better understand and fight these fatal diseases. This review summarizes the achievements of the different groups and outlines prospects for future research. Basic research deals with the etiopathogenesis of motor neuron diseases. In vitro and in vivo models of superoxide dismutase 1 (SOD1) mutations are used to investigate the mechanisms of motor neuron death associated with this gene defect. The role of excitotoxicity, immune response, intracellular aggregates and mitochondrial alterations is studied with an integrated approach, at the molecular and cellular levels. Transgenic mice carrying the human mutated SOD1, and the wobbler mouse, a spontaneous model for motor neuron degeneration, offer unique opportunities for testing new therapies in vivo related or not to SOD1 mutations. Clinical research has focused mostly on the incidence and determinants of ALS in several areas of Italy. The incidence of the disease is now among the highest according to the results of population-based regional registries. Compared to earlier studies, more recent Italian investigations show an increase in the incidence and mortality related to ALS. Findings on the role of environmental risk factors are inconsistent. Methodological issues have also been raised by Italian groups regarding the diagnosis and treatment. The validity of the El Escorial diagnostic classification has been questioned where investigators and carers have not received formal training. Pitfalls and methodological drawbacks of randomized clinical trials have been highlighted based on the results of collaborative trials by Italian investigators. Information is now available on non-pharmacological treatments and palliative care, and the economic aspects and quality of life of ALS patients are being investigated.
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PMID:Basic and clinical research on amyotrophic lateral sclerosis and other motor neuron disorders in Italy: recent findings and achievements from a network of laboratories. 1519 3


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