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

To investigate the molecular mechanisms of the 'gain of toxic function' of mutant Cu/Zn superoxide dismutase (SOD) associated with familial amyotrophic lateral sclerosis (FALS), mutant (Ala 4 --> Thr, Gly 85 --> Arg, Gly 93 --> Ala, and two base-pair deletion in the 126th codon), as well as wild-type (wt), Cu/Zn SODs were expressed in COS7 cells. The formation of granular cytoplasmic aggregates accompanied by collapse of the cytoplasm was observed in cells expressing mutant (mt) Cu/Zn SODs, but not in cells expressing wt Cu/Zn SOD. The aggregates contained ribosome-like particles and endoplasmic reticulum. These results suggest the possibility that mt Cu/Zn SODs promote the formation of aggregates which are toxic to cells.
 ...
PMID:Formation of granular cytoplasmic aggregates in COS7 cells expressing mutant Cu/Zn superoxide dismutase associated with familial amyotrophic lateral sclerosis. 985 58

Riluzole is used clinically in patients with amyotrophic lateral sclerosis. As oxidative stress, in addition to excitotoxicity, may be a major mechanism of motoneuron degeneration in patients with amyotrophic lateral sclerosis, we examined whether riluzole protects against nonexcitotoxic oxidative injury. Probably reflecting its weak antiexcitotoxic effects, riluzole (1-30 microM) attenuated submaximal neuronal death induced by 24-h exposure to 30 microM kainate or NMDA, but not that by 100 microM NMDA, in cortical cultures. Riluzole also attenuated nonexcitotoxic oxidative injury induced by exposure to FeCl3 in the presence of MK-801 and CNQX. Consistent with its antioxidative effects, riluzole reduced Fe3+-induced lipid peroxidation, and inhibited cytosolic phospholipase A2. By contrast, riluzole did not attenuate neuronal apoptosis induced by staurosporine. Rather unexpectedly, 24-48-h exposure to 100-300 microM riluzole induced neuronal death accompanied by nuclear and DNA fragmentations, which was attenuated by caspase inhibitor carbobenzyloxy-Val-Ala-Asp-fluoromethyl ketone but not by protein synthesis inhibitor cycloheximide. The present study demonstrates that riluzole has direct antioxidative actions, perhaps in part by inhibiting phospholipase A2. However, in the same neurons, riluzole paradoxically induces neuronal apoptosis in a caspase-sensitive manner. Considering current clinical use of riluzole, further studies are warranted to investigate its potential cytolethal effects.
 ...
PMID:Antioxidative and proapoptotic effects of riluzole on cultured cortical neurons. 993 Jul 45

Mutations of the SOD1 gene (formerly known as Cu,Zn-SOD) are frequently associated with the familial form of amyotrophic lateral sclerosis (ALS). The G93A mutation of SOD1 with substitution of Gly to Ala at residue 93 results in gain of a peroxidative function. Here we report that transfection of PC12 neuron precursor cells with the G93A mutation of SOD1 results in increased production of hydroxyl radicals (*OH) and an enhanced rate of cell death by apoptosis. Notably, PC12 cells transfected with the H63C/G93A mutant of SOD1 with a mutation in the catalytic site that converts histidine at position 63 to cysteine showed a dramatically reduced production of *OH and rate of death by apoptosis. Thus the gain of function of the mutant G93A SOD1 can be reduced by an active site mutation. These results provide additional genetic evidence for the hypothesis that the increased *OH production and induced cytotoxicity in neuron cells expressing the mutant G93A SOD1 results from the gain of peroxidative function by the enzyme's catalytic site.
 ...
PMID:Increased hydroxyl radical production and apoptosis in PC12 neuron cells expressing the gain-of-function mutant G93A SOD1 gene. 995 97

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.
 ...
PMID:Beneficial effects of lysine acetylsalicylate, a soluble salt of aspirin, on motor performance in a transgenic model of amyotrophic lateral sclerosis. 1007 99

Transgenic mice that express a mutant Cu/Zn superoxide dismutase (SOD1) gene have been provided a valuable model for human amyotrophic lateral sclerosis (ALS). We studied a possible impairment of fast axonal transport in transgenic mice carrying a Gly93-->Ala (G93A) mutant SOD1 gene found in human familial ALS (FALS). Left sciatic nerve was ligated for 6 h in transgenic (Tg) and age-matched wild-type (WT) mice. Immunohistochemical analyses were performed for accumulations of kinesin and cytoplasmic dynein on both sides of the ligation site. Clinical function and histology in the spinal cords, sciatic nerves and gastrocnemius muscles were also assessed. The mice were examined at an early asymptomatic stage (aged 19 weeks) and a late stage (30 weeks) just before the development of the symptoms. WT mice showed an apparent increase in immunoreactivities for kinesin and cytoplasmic dynein at proximal and distal of the ligation, respectively. In contrast, the young Tg mice showed a selective decrease of kinesin accumulation in the proximal of the ligation. The mice were asymptomatic with a mild histological change only in muscles. The old Tg mice showed a marked reduction of the immunoreactivity for kinesin and cytoplasmic dynein on both sides of the ligation. They had a significant loss of spinal motor neurons, relatively small myelinated fiber densities of sciatic nerves, and severe muscular changes. These results provide direct evidence that the SOD1 mutation leads to impaired fast axonal transport, particularly in the anterograde direction at an early, asymptomatic stage preceding loss of spinal motor neurons and peripheral axons. This impairment may contribute to subsequent selective motor neuron death in the present model implicated for human FALS.
 ...
PMID:Selective impairment of fast anterograde axonal transport in the peripheral nerves of asymptomatic transgenic mice with a G93A mutant SOD1 gene. 1008 67

To determine the role of advanced glycation endproducts (AGE) in the pathogenesis of familial amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) mutation, we investigated the immunohistochemical localization of N(epsilon)-carboxymethyl-lysine (CML), one of the major AGE structures, in spinal cords from three familial ALS patients with a heterozygous Ala to Val substitution at codon 4 in the gene for SOD1. Neuronal hyaline inclusions (NHIs), the abnormal structures seen in some of the remaining lower motor neurons of familial ALS patients with SOD1 mutation, were intensely stained by a monoclonal antibody specific for CML in contrast to the only weakly stained cytoplasm. Immunoelectron microscopy depicted the CML determinants restricted to the granule-associated thick linear structures that mainly compose the NHIs. The NHIs were also recognized by antibodies to SOD1, phosphorylated neurofilament protein and ubiquitin. No focal collection of either CML or SOD1 was found in neurons of the control individuals. Our results indicate that CML is a component of the NHIs of familial ALS patients with SOD1 mutation, and suggest that the CML formation may be mediated by protein glycoxidation or lipid peroxidation in the presence of oxidative stress from mutant SOD1, in association with motor neuron degeneration.
 ...
PMID:Advanced glycation endproducts are deposited in neuronal hyaline inclusions: a study on familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation. 1009 Jun 70

Point mutations of Cu,Zn-superoxide dismutase (SOD) have been linked to familial amyotrophic lateral sclerosis (FALS). We reported that the Swedish FALS Cu,Zn-SOD mutant, D90A, exhibited an enhanced hydroxyl radical-generating activity, while its dismutation activity was identical to that of the wild-type enzyme (Kim et al. 1998a; 1998b). Transgenic mice that express a mutant Cu,Zn-SOD, Gly93 --> Ala (G93A), have been shown to develop amyotrophic lateral sclerosis (ALS) symptoms. We cloned the cDNA for the FALS G93A mutant, overexpressed the protein in E. coli cells, purified the protein, and studied its enzymic activities. Our results showed that the G93A, the D90A, and the wild-type enzymes have identical dismutation activity. However, the hydroxyl radical-generating activity of the G93A mutant was enhanced relative to those of the D90A and the wild-type enzyme (wild-type < D90A < G93A). These higher free radical-generating activities of mutants facilitated the release of copper ions from their own molecules (wild-type < D90A < G93A). The released copper ions can enhance the Fenton-like reaction to produce hydroxyl radicals and play a major role in the oxidative damage of macromolecules. Thus, the FALS symptoms may be associated with the enhancements in both the free radical-generating activity and the releasing of copper ions from the mutant enzyme.
 ...
PMID:Release of copper ions from the familial amyotrophic lateral sclerosis-associated Cu,Zn-superoxide dismutase mutants. 1010 80

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.
 ...
PMID:Lack of involvement of neuronal nitric oxide synthase in the pathogenesis of a transgenic mouse model of familial amyotrophic lateral sclerosis. 1033 14

Mutations in superoxide dismutase 1 (SOD1) polypeptides cause a form of familial amyotrophic lateral sclerosis (FALS). In different kindreds, harboring different mutations, the duration of illness tends to be similar for a given mutation. For example, patients inheriting a substitution of valine for alanine at position four (A4V) average a 1.5 year life expectancy after the onset of symptoms, whereas patients harboring a substitution of arginine for histidine at position 46 (H46R) average an 18 year life expectancy after disease onset. Here, we examine a number of biochemical and biophysical properties of nine different FALS variants of SOD1 polypeptides, including enzymatic activity (which relates indirectly to the affinity of the enzyme for copper), polypeptide half-life, resistance to proteolytic degradation and solubility, in an effort to determine whether a specific property of these enzymes correlates with clinical progression. We find that although all the mutants tested appear to be soluble, the different mutants show a remarkable degree of variation with respect to activity, polypeptide half-life and resistance to proteolysis. However, these variables do not stratify in a manner that correlates with clinical progression. We conclude that the basis for the different life expectancies of patients in different kindreds of sod1-linked FALS may result from an as yet unidentified property of these mutant enzymes.
 ...
PMID:Variation in the biochemical/biophysical properties of mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial amyotrophic lateral sclerosis kindreds. 1040 Sep 92

Dominant mutations in the copper/zinc superoxide dismutase (SOD1) gene have been observed in 15-20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism by which SOD1 mutations result in motor neuron degeneration in FALS mice partly involves oxidative damage and an increased peroxidase activity of the mutant SOD1. A new therapeutic approach designed to eliminate the substrate of this peroxidase activity was examined in two lines of transgenic mice expressing the FALS-linked mutation glycine to alanine (G93A). We investigated the ability of putrescine-modified catalase (PUT-CAT), an antioxidant enzyme that removes hydrogen peroxide and has increased permeability at the blood-brain barrier, to modify the time course of the SOD1 mutation-induced motor neuron disease in these FALS mice. Continuous, subcutaneous administration of PUT-CAT significantly delayed the age at which onset of clinical disease occurred (indicated by loss of splay and/or tremors of hindlimbs) in a high-expressor line of FALS transgenic mice. Intraperitoneal injection of PUT-CAT given two times per week also significantly delayed the onset of clinical disease in a low-expressor line of FALS mice. PUT-CAT also significantly delayed the age at which clinical weakness developed (quantified by measuring the shortening of stride length) in both lines of FALS animals. No significant changes were observed in the survival times of the high-expressor FALS mice in any of the treatment groups. However, a trend toward a prolongation of survival was observed in the PUT-CAT-treated low-expressor FALS mice. These results support the role of free radical-mediated damage in the cascade of events leading to motor neurodegeneration in FALS and indicate that PUT-CAT interacts with a critical step in this cascade to delay the onset of clinical disease as well as the development of clinical weakness in FALS transgenic mice.
 ...
PMID:Therapeutic benefits of putrescine-modified catalase in a transgenic mouse model of familial amyotrophic lateral sclerosis. 1048 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>