Rapid Progression of Sporadic ALS in a Patient Carrying SOD1 p.Gly13Arg Mutation

Amyotrophic lateral sclerosis (ALS), the most common adult onset motor neuron disease, is pathologically characterized by progressive loss of the upper and lower motor neurons. Mutations in the Cu/Zn superoxide dismutase gene (SOD1) account for about 20% of familial ALS cases and a small percentage of sporadic ALS (SALS) cases, and have revealed a validated genotype-phenotype correlation. Herein, we report a p.Gly13Arg mutation in SOD1 exon 1 in a patient with SALS who presented with a rapidly progressive course, predominantly affecting the lower motor neurons. A 48-year-old man presented with progressive weakness and muscle atrophy of the left upper and lower limbs, followed by muscle fasciculation and cramping. The clinical features of the patient were clearly suggestive of ALS, and implied a sporadic form with rapid progression, predominantly affecting the lower motor neurons. Sequencing of the SOD1 gene by PCR revealed a missense mutation of G to C (c.37G>C) in exon 1, and amino acid substitution of glycine by arginine (p.Gly13Arg). This is the first case identifying the p.Gly13Arg mutation of SOD1 in the Korean population, and clinical assessments of this patient revealed a different phenotype compared with other cases.

Treadmill exercise prevents diabetes-induced increases in lipid peroxidation and decreases in Cu,Zn-superoxide dismutase levels in the hippocampus of Zucker diabetic fatty rats

In the present study, we investigated the effects of treadmill exercise on lipid peroxidation and Cu,Zn-superoxide dismutase (SOD1) levels in the hippocampus of Zucker diabetic fatty (ZDF) rats and lean control rats (ZLC) during the onset of diabetes. At 7 weeks of age, ZLC and ZDF rats were either placed on a stationary treadmill or made to run for 1 h/day for 5 consecutive days at 16~22 m/min for 5 weeks. At 12 weeks of age, the ZDF rats had significantly higher blood glucose levels and body weight than the ZLC rats. In addition, malondialdehyde (MDA) levels in the hippocampus of the ZDF rats were significantly higher than those of the ZLC rats whereas SOD1 levels in the hippocampus of the ZDF rats were moderately decreased. Notably, treadmill exercise prevented the increase of blood glucose levels in ZDF rats. In addition, treadmill exercise significantly ameliorated changes in MDA and SOD1 levels in the hippocampus although SOD activity was not altered. These findings suggest that diabetes increases lipid peroxidation and decreases SOD1 levels, and treadmill exercise can mitigate diabetes-induced oxidative damage in the hippocampus.

Associação da concentração plasmática de cobre com metaloproteínas cobre-dependentes em atletas de elite / Association between copper plasma concentration and copper-dependent metaloproteins in elite athletes

O cobre é um elemento-traço essencial para a manutenção de vários processos biológicos, tais como metabolismo energético, homeostase de ferro e mecanismos de proteção antioxidante através da atividade da cobre-zinco superóxido dismutase (Cu-Zn SOD), da ceruloplasmina e da metalotioneína. No entanto, o cobre também participa de reações oxidativas que promovem a liberação de radicais livres, podendo prejudicar a integridade e a funcionalidade celular. A atividade física afeta a homeostase do cobre e promove maior utilização de oxigênio, favorecendo a instalação do estresse oxidativo quando mecanismos naturais de proteção antioxidante, incluindo os dependentes de cobre, não atuam adequadamente. Não há relatos na literatura sobre a associação de diferentes níveis de concentração plasmática de cobre com indicadores antioxidantes cobre-dependentes em atletas de elite. O presente estudo objetivou verificar a associação entre diferentes níveis plasmáticos de cobre e metaloproteínas cobre-dependentes, com atividade antioxidante, em atletas de elite. Os indicadores bioquímicos (metalotioneína e Cu-Zn SOD eritrocitárias, ceruloplasmina e cobre plasmáticos) foram avaliados em 50 atletas, homens e adultos, utilizando metodologias já consolidadas. Os resultados mostraram que 32 por cento dos atletas apresentaram níveis de cobre plasmático inferiores a 11µmol/L, 38 por cento entre 11-13µmol/L e 30 por cento > 13µmol/L. As associações encontradas entre cobre plasmático e ceruloplasmina (r = 0,31; p = 0,04) e Cu-Zn SOD (r = 0,32, p = 0,02); metalotioneína eritrocitária e ceruloplasmina (r = 0,40, p = 0,006) e Cu-Zn SOD (0,73, p = 0,001) e entre Cu-Zn SOD e ceruloplasmina (r = 0,37, p < 0,001) demonstraram que a atividade da Cu-Zn SOD e a concentração de metalotioneína eritrocitárias são sensíveis a menor concentração, enquanto que a ceruloplasmina é sensível a elevadas concentrações plasmáticas de cobre, sugerindo que há um equilíbrio homeostático entre...

Copper is a trace element essential in several biological processes, some of them important for physical activity, such as energy metabolism, iron homeostasis and antioxidant protection through the plasma ceruloplasmin, erythrocyte Cu-Zn superoxide dismutase (Cu-Zn SOD) and metallothionein. However, copper also participates in oxidative reactions releasing free radicals, which may adversely affect cell integrity and function. Physical activity is known to affect copper homeostasis and may interfere in the copper antioxidant capacity. Intense physical activity results in higher oxygen consumption, which favors the release of free radicals and may cause irreversible damage to the body when the natural mechanisms of protection, including those copper-dependent, are not properly stimulated. Few studies related exercise with plasma copper level and copper-dependent metalloproteins in elite athletes. The present study aimed at evaluating the association between different levels of plasma copper and copper-dependent metalloproteins in male elite athletes (n = 50). The biochemical indices studied were plasma copper and ceruloplasmin, and erythrocyte Cu-Zn superoxide dismutase and metallothionein by validated methods. The results showed that 32 percent of the athletes had plasma copper levels lower than 11µmol/L, 38 percent between 11-13 µmol/L and 30 percent higher than 13 µmol/L. Plasma copper was associated with plasma ceruloplasmin level (r = 0.31, p = 0.004), and with Cu-Zn SOD (r = -0.32, p = 0.02); metallothionein erythrocyte were associated with Cu-Zn SOD (r = 0.73, p = 0.001) and with ceruloplasmin (r = 0.40, p = 0.006). These results suggest that both plasma and erythrocyte antioxidant capacity favor homeostatic adjustments in agreement with plasma copper levels in elite athletes.

Mutation Site of Cu/Zn superoxide dismutase in an amyotrophic lateral sclerosis family / 医学研究生学报

Objective: To identify the mutation points of Cu/Zn superoxide dismutase(SOD1) gene in an amyotrophic lateral sclerosis(ALS) family with a unique phenotype,and to compare the value of single strand conformation polymorphism(SSCP) and denaturing high performance liquid chromatography(DHPLC). Methods: Five exons of SOD1 gene were amplified by PCR. The difference of these products were analyzed by PCR-SSCP and DHPLC.DNA sequencing was used to examine the mutation. Results: ①Mutations were found in exons 2 and 5 in several family members.DNA sequencing revealed that a base pair insertion occurred in the codon area of exon 2 and in the non-codon area of exon 5.②The results of DHPLC tests proved double peaks in one member with ALS symptoms(Ⅲ1),which indicated the possibility of mutation in SOD1 exon 4.DNA sequencing revealed that there was a heterozygote,with a mutation of GAA to GGA in exon 4 in the member with double peak. Conclusion: ①The mutations in exons 2,4,5 were proved.Insertion of exon 2 may be responsible for the disease of the ALS family in Chongqing.②Compared with PCR-SSCP,DHPLC technique has been proven to be a rapid and reliable method for screening mutation site in large samples.

Denaturing high performance liquid chromatography for detection of point mutation of familial ALS / 第三军医大学学报

Objective To identify the point mutation of Cu/Zn superoxide dismutase(SOD1) gene in an amyotrophic lateral sclerosis(ALS) family and observe the value of denaturing high performance liquid chromatography(DHPLC). Methods DHPLC and DNA sequencing were used to examine SOD1 gene of the ALS family which had not been found mutation by PCR-SSCP. Results DHPLC tests proved double peaks in one member(Ⅲ_1), Which indicated the possibility of mutation in SOD1 exon 4. DNA sequencing revealed that there was a heterozygote,with mutation of GAA to GGA in exon 4, and with a substitution of glutacid by glycine. Conclusion As compared with PCR-SSCP, DHPLC technique has proved to be a rapid and reliable method for screening mutation site in large samples.

Neuroprotective Effect of Estrogen on Motor Neuron Cells Expressing Wild Type or Mutant Cu/Zn Superoxide Dismutase

BACKGROUND: Recently, the mechanism involved in nitric oxide (NO)-mediated motor neuron death is under extensive investigation. The role of Cu/Zn superoxide dismutase (SOD) mutation, which is found in about 2% of all ALS patients, has been implicated in selective motor neuron death and it is said to play an important role in NO-mediated motor neuron death. Estrogen is reported to have neuroprotective effect in various neurological diseases. However, neuroprotective effect on estradiol on spinal motor neuron exposed to NO has rarely been studied. METHODS: Motor neuron-neuroblastoma hybrid cell expressing wild-type or mutant (G93A or A4V) SOD gene was treated with 200 micro M Snitrosoglutathione. After 24 hours, cell viability was measured by MTT assay. To see the neuroprotective effect of estradiol, pretreatment with 5 nM or 50 nM 17 beta-estradiols was done 24 hours before S-nitrosoglutathione treatment. RESULTS: S-nitrosoglutathione showed significant neurotoxic effect in all three cell lines. Percentage of cell death was significantly different in each cell line. Both 5 nM and 50 nM estradiols showed neuroprotective effect in G93A cell line. In wild-type cell line, 50 nM estradiol showed neuroprotective effect, but 5 nM estradiol did not. In A4V cell line, estradiol did not showed neuroprotective effect. CONCLUSIONS: This study showed that NO-mediated motor neuron death could be influenced by presence or absence of mutation and type of mutation in SOD gene. Neuroprotective effect of estradiol is also influenced by SOD gene mutation. This study implies that estrogen might be beneficial to some ALS patients.

Therapeutic potential of madecassoside in transgenic mice of amyotrophic lateral sclerosis / 中草药

Objective To investigate the therapeutic potential of madecassoside in mice expressing a mutant human Cu,Zn superoxide dismutase(SOD1)-G93A linked to human amyotrophic lateral sclerosis(ALS).Methods Effects of madecassoside on onset of clinical disease,survival of mice,decline of motor function,and motor neuron(MN) degeneration were observed by behavioral analysis and histological eva-(luation.) Results Madecassoside(61.1?11.0) and(185.6?18.7) mg/(kg?d) ig administration,beginning at 70 d of age until death,prolonged survival of SOD1-G93A ALS mice by 11.4 and 9.4 d,respectively(P