UMLS:C0002736 - FACTA Search

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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the effect of lysine acetylsalicylate (LAS; Aspegic), a soluble salt of aspirin, on motor deficits in transgenic mice expressing a human superoxide dismutase SOD1 mutation (Gly-93 --> Ala), an animal model of familial amyotrophic lateral sclerosis (FALS). In nontreated FALS mice, motor impairments appear at 12-14 weeks of age, whereas paralysis is not observed before 20 weeks of age. Life expectancy is 140-170 days. Early treatment with LAS from 5 weeks of age delayed the appearance of motor deficits in FALS mice as measured by extension reflex, loaded grid, and rotarod tests. This beneficial effect of treatment was maintained up to 18 weeks of age, until just before onset of end-stage disease. When treatment was started at 13 weeks, no significant beneficial effect was observed. These results demonstrate that chronic LAS treatment is able to delay the appearance of reflex, coordination, and muscle strength deficits in this animal model of ALS if the treatment is started early enough. However, neither the onset of paralysis nor end-stage disease were improved by the LAS treatment. In the absence of an effect on survival, the functional improvement demonstrated here is probably the maximum that this demanding model could allow. Although other properties of LAS may have contributed to its beneficial effect, we suggest that the antioxidant properties of aspirin are responsible for the positive effects in this model and support the use of antioxidants as effective therapy for ALS.
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PMID:Beneficial effects of lysine acetylsalicylate, a soluble salt of aspirin, on motor performance in a transgenic model of amyotrophic lateral sclerosis. 1007 99

A subset of familial cases of amyotrophic lateral sclerosis are linked to missense mutations in copper/zinc superoxide dismutase type 1. Patients with missense mutations in copper/zinc superoxide dismutase type 1 develop a paralytic disease indistinguishable from sporadic amyotrophic lateral sclerosis through an unknown toxic gain of function. Nitric oxide reacts with the superoxide anion to form the strong oxidant, peroxynitrite, which participates in neuronal injury in a variety of model systems. Peroxynitrite is an alternate substrate for copper/zinc superoxide dismutase type 1, causing catalytic nitration of tyrosine residues in other proteins. Mutations in copper/zinc superoxide dismutase type 1 may disrupt the active site of the enzyme and permit greater access of peroxynitrite to copper, leading to increased nitration by peroxynitrite of critical cellular targets. To investigate whether neuronal-derived nitric oxide plays a role in the pathogenesis of familial amyotrophic lateral sclerosis, we examined the effects of three different nitric oxide synthase inhibitors: a non-selective nitric oxide synthase inhibitor, nitro-L-arginine methyl ester; a relatively selective inhibitor of neuronal nitric oxide synthase, 7-nitroindazole; and a novel highly selective neuronal nitric oxide synthase inhibitor, AR-R 17,477, in transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 (Gly-->Ala at position 93; G93A) containing a high transgene copy number and a low transgene copy number. AR-R 17,477, but not nitro-L-arginine methyl ester or 7-nitroindazole, significantly prolonged survival in both the high and low transgene transgenic mice. To determine whether neuronal nitric oxide synthase is involved in the pathogenesis resulting from the familial amyotrophic lateral sclerosis copper/zinc superoxide dismutase type 1 mutation, we produced mice with the copper/zinc superoxide dismutase type 1 mutation which lack the neuronal nitric oxide synthase gene. The transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 on neuronal nitric oxide synthase null background do not live significantly longer than transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1. Western blot analysis indicates the presence of two neuronal nitric oxide synthase-like immunoreactive bands in spinal cord homogenates of the neuronal nitric oxide synthase null mice, and residual neuronal nitric oxide synthase catalytic activity ( > 7%) is detected in the spinal cord of the transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 on neuronal nitric oxide synthase null background. This amount of residual activity probably does not account for lack of protection afforded by the disrupted neuronal nitric oxide synthase gene in the familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 mice. Immunological nitric oxide synthase is not detected in the copper/zinc superoxide dismutase type 1 mutant mice at several different ages, thus excluding immunological nitric oxide synthase as a contributor to the pathogenesis of familial amyotrophic lateral sclerosis. Levels of neuronal nitric oxide synthase as well as Ca2+-dependent nitric oxide synthase catalytic activity in the copper/zinc superoxide dismutase type 1 mutant mice do not differ from wild type mice. Endothelial nitric oxide synthase levels may be decreased in the copper/zinc superoxide dismutase type 1 mutant mice. Together, these results do not support a significant role for neuronal-derived nitric oxide in the pathogenesis of familial amyotrophic lateral sclerosis transgenic mice.
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PMID:Lack of involvement of neuronal nitric oxide synthase in the pathogenesis of a transgenic mouse model of familial amyotrophic lateral sclerosis. 1033 14

The presence of the copper ion at the active site of human wild type copper-zinc superoxide dismutase (CuZnSOD) is essential to its ability to catalyze the disproportionation of superoxide into dioxygen and hydrogen peroxide. Wild type CuZnSOD and several of the mutants associated with familial amyotrophic lateral sclerosis (FALS) (Ala(4) --> Val, Gly(93) --> Ala, and Leu(38) --> Val) were expressed in Saccharomyces cerevisiae. Purified metal-free (apoproteins) and various remetallated derivatives were analyzed by metal titrations monitored by UV-visible spectroscopy, histidine modification studies using diethylpyrocarbonate, and enzymatic activity measurements using pulse radiolysis. From these studies it was concluded that the FALS mutant CuZnSOD apoproteins, in direct contrast to the human wild type apoprotein, have lost their ability to partition and bind copper and zinc ions in their proper locations in vitro. Similar studies of the wild type and FALS mutant CuZnSOD holoenzymes in the "as isolated" metallation state showed abnormally low copper-to-zinc ratios, although all of the copper acquired was located at the native copper binding sites. Thus, the copper ions are properly directed to their native binding sites in vivo, presumably as a result of the action of the yeast copper chaperone Lys7p (yeast CCS). The loss of metal ion binding specificity of FALS mutant CuZnSODs in vitro may be related to their role in ALS.
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PMID:Loss of in vitro metal ion binding specificity in mutant copper-zinc superoxide dismutases associated with familial amyotrophic lateral sclerosis. 1062 39

Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) underlie some familial cases of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by loss of cortical, brainstem and spinal motoneurons. Transgenic mice over- expressing a mutated form of human SOD1 containing a Gly-->Ala substitution at position 93 (SOD1(G93A)) develop a severe, progressive motoneuron disease. We investigated the potential of recombinant adeno-associated virus (rAAV) to transfer neuroprotective molecules in this animal ALS model. Initial experiments showed that injection of an rAAV vector encoding green fluorescent protein unilaterally into the lumbar spinal cord of wild-type mice leads to expression of the reporter gene in 34.7 +/- 5.2% of the motoneurons surrounding the injection site. Intraspinal injection of an rAAV encoding the anti-apoptotic protein bcl-2 in SOD1 (G93A) mice resulted in sustained bcl-2 expression in motoneurons and significantly increased the number of surviving motoneurons at the end-stage of disease. Moreover, the compound muscle action potential amplitude elicited by nerve stimulation and recorded by electromyographic measurements was higher in the rAAV-bcl-2-treated group than in controls. Local bcl-2 expression in spinal motoneurons delayed the appearance of signs of motor deficiency but was not sufficient to prolong the survival of SOD1 (G93A) mice. To our know-ledge, this study describes the first successful transduction and protection of spinal motoneurons by direct gene transfer in a model of progressive motoneuron disease. Our results support the use of AAVs for the delivery of protective genes to spinal cord moto-neurons as a possible way to enhance motoneuron survival and repair.
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PMID:Increased motoneuron survival and improved neuromuscular function in transgenic ALS mice after intraspinal injection of an adeno-associated virus encoding Bcl-2. 1074 88

In the present study we analyze the molecular mechanisms underlying motor neuron degeneration in familial amyotrophic lateral sclerosis (FALS). For this, we used a transgenic mouse model expressing the Cu/Zn superoxide dismutase (SOD1) gene with a Gly(86) to Arg (G86R) mutation equivalent to that found in a subset of human FALS. Using an optimized suppression subtractive hybridization method, a cDNA specifically up-regulated during the asymptomatic phase in the lumbar spinal cord of G86R mice was identified by sequence analysis as the KIF3-associated protein (KAP3), a regulator of fast axonal transport. RT-PCR analysis revealed that KAP3 induction was an early event arising long before axonal degeneration. Immunohistochemical studies further revealed that KAP3 protein predominantly accumulates in large motor neurons of the ventral spinal cord. We further demonstrated that KAP3 up-regulation occurs independent of any change in the other components of the kinesin II complex. However, since the ubiquitous KIF1A motor is up-regulated, our results show an early and complex rearrangement of the fast axonal transport machinery in the course of FALS pathology.
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PMID:Differential screening of mutated SOD1 transgenic mice reveals early up-regulation of a fast axonal transport component in spinal cord motor neurons. 1096

Transplantation of hNT Neurons derived from the human teratocarcinoma cell-line (NTera2/D1) has been shown to ameliorate motor dysfunction in a number of injury or disease models in which the deficits are fairly localized. However, these cells have not been used before in a model with more extensive neurodegeneration. The aim of this study is to determine the effects of hNT Neuron transplants on motor neuron function in a mouse model of familial amyotrophic lateral sclerosis (FALS) in which there is a substitution of Alanine for Glycine at position 93 of the human SOD1 gene (G93A). Amyotrophic lateral sclerosis is a fatal degenerative motor neuron disease affecting the spinal cord, brainstem, and cortex. This disease clinically manifests as progressive muscular weakness and atrophy, leading to paralysis and death within 3-5 years of diagnosis. The FALS represents 10-13% of all cases. A range of behavioral tests was used to examine spontaneous locomotor activity, coordination, and muscle strength of mice. Long-term (10-11 weeks) transplantation of hNT Neurons into the L(4)-L(5) segments of the ventral horn spinal cord of FALS(G93A) mice at 7 weeks of age (before onset of overt behavioral symptoms of disease) delayed the onset of motor dysfunction for at least 3 weeks. The average lifespan of the transplanted mice was 128 days compared to 106 days for media-injected group. The last mouse in the hNT Neuron transplanted group was euthanized at 135 days of age when it display partial paralysis of the hindlimbs. Immunohistochemical analysis of the implanted spinal cords demonstrated the survival of grafted hNT Neurons and showed many healthy-appearing motor neurons near the implant site. These results suggest that hNT Neuron transplantation may be a promising therapeutic strategy for ALS.
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PMID:Positive effect of transplantation of hNT neurons (NTera 2/D1 cell-line) in a model of familial amyotrophic lateral sclerosis. 1192 59

Although excitotoxic and oxidative stress play important roles in spinal neuron death, the exact mechanisms are not fully understood. We examined cell damage of primary culture of 11-day-old rat spinal cord by addition of glutamate, nitric oxide (NO) or peroxynitrite (PN) with detection of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL). With addition of glutamate, NOC18 (a slow NO releaser) or PN, TUNEL positive nuclei were found in spinal large motor neurons from 24 h, and the positive cell proportion greatly increased at 48 h in contrast to the vehicle. The present results suggest that both excitotoxic and oxidative stress play important role in the apoptotic pathway in cultured rat spinal neurons. To examine a possible protective effect of exogenous glial cell line-derived neurotrophic factor (GDNF) gene expression in transgenic (Tg) mice carrying a Gly 93Ala (G93A) mutant SOD1 gene found in human familial ALS, a replication defective adenoviral vector containing GDNF gene was directly injected unilaterally into leg muscles. There were significantly more large motoneurons in GDNF-treated Tg mice than in untreated and Ad-Laz-treated group. The number of large motoneurons in GDNF-treated side of Tg mice were significantly more than that in untreated side. These observations demonstrate that GDNF gene therapy in a mouse model of FALS promotes the survival of motoneurons, suggesting that a similar approach might delay the progression of neurodegeneration of ALS.
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PMID:[Gene therapy and neurotrophic factor treatment for amyotrophic lateral sclerosis]. 1223 26

The release of [(3)H]D-aspartate ([(3)H]D-ASP) or [(3)H]GABA evoked by glycine from spinal cord synaptosomes was compared in mice expressing mutant human SOD1 with a Gly(93) Ala substitution ([SOD1-G93A(+)]), a transgenic model of amyotrophic lateral sclerosis, and in control mice. Mice expressing mutated SOD1 were killed at the advanced phase of the pathology, when they showed signs of ingestion disability, because of paralysis of the posterior limbs. In control mice glycine concentration-dependently evoked [(3)H]D-ASP and [(3)H]GABA release. Potentiation of the spontaneous release of both amino acids is likely to be mediated by activation of a glycine transporter, since the effects of glycine were counteracted by the glycine transporter blocker glycyldodecylamide but not by the glycine receptor antagonists strychnine and 5,7-dichlorokynurenate. The glycine-evoked release of [(3)H]D-ASP, but not that of [(3)H]GABA, was significantly more pronounced in SOD1-G93A(+) than in control animals.
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PMID:Activation of a glycine transporter on spinal cord neurons causes enhanced glutamate release in a mouse model of amyotrophic lateral sclerosis. 1268 56

Amaranthus blitoides S. Watson (prostrate pigweed) populations resistant to acetolactate synthase (ALS; EC 4.1.3.18)-inhibiting herbicides and triazines (SuR/TR) were found in Israel. The Ganot population was 6- to 790-fold more resistant to ALS inhibitors than the wild type due to an altered target site. Molecular analyses showed that the Ganot population was a mixture of two biotypes: (i) SuRA/TR in which domain A of the als gene differed in one nucleotide, resulting in substitution of Pro by Ser 188; (ii) SuRB/TR in which a mutation in domain B led to a substitution of Trp by Leu 569. The mutation in domain A resulted in resistance to all ALS inhibitors except imidazolinones, whereas the mutation in domain B led to resistance to all ALS inhibitors tested. SuRA/TR and SuRB/TR are multiple-resistant with an additional single mutation in the plastidic psbA gene that changes Ser 264 to Gly in the D1 protein, leading to triazine resistance. It is evident that plants within a population exposed to a similar selection pressure may show different patterns of cross-resistance due to three different point mutations. This unique phenomenon renders planning of rational weed management difficult or even impossible.
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PMID:Molecular basis for multiple resistance to acetolactate synthase-inhibiting herbicides and atrazine in Amaranthus blitoides (prostrate pigweed). 1268 70

Apart from the extensive loss of motor neurons, degeneration of midbrain dopaminergic cells has been described in both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Mice overexpressing the mutant human Cu/Zn superoxide dismutase (SOD1) show an ALS-like phenotype in that they show a progressive death of motor neurons accompanied by degeneration of dopaminergic cells. To describe the functional alterations specifically associated with this dopaminergic dysfunction, we have investigated the corticostriatal synaptic plasticity in mice overexpressing the human SOD1 (SOD1+) and the mutated (Gly(93)-->Ala) form (G93A+) of the same enzyme. We show that repetitive stimulation of the corticostriatal pathway generates long-term depression (LTD) in SOD1+ mice and in control (G93A-/SOD1-) animals, whereas in G93A+ mice the same stimulation generates an N-methyl-D-aspartic acid receptor-dependent long-term potentiation. No significant alterations were found in the intrinsic membrane properties of striatal medium spiny neurons and basal corticostriatal synaptic transmission of G93A+ mice. Bath perfusion of dopamine or the D(2) dopamine receptor agonist quinpirole restored LTD in G93A+ mice. Consistent with these in vitro results, habituation of locomotor activity and striatal-dependent active avoidance learning were impaired in G93A+ mice. Thus, degeneration of dopaminergic neurons in the substantia nigra of G93A+ mice causes substantial modifications in striatal synaptic plasticity and related behaviors, and may be a cellular substrate of the extrapyramidal motor and cognitive disorders observed in familial and sporadic ALS.
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PMID:Altered long-term corticostriatal synaptic plasticity in transgenic mice overexpressing human CU/ZN superoxide dismutase (GLY(93)-->ALA) mutation. 1269 76

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