Zn Superoxide Dismutase Mutation Research Articles

Oxidative stress and metal content in blood and cerebrospinal fluid of amyotrophic lateral sclerosis patients with and without a Cu, Zn-superoxide dismutase mutation

Hydroxyl radical, ascorbate free radical, superoxide dismutase (SOD) activities, Cu,Zn-SOD protein, Mn-SOD protein, 8-hydroxy-2' -deoxyguanosine (8-OHdG) and metals were compared in red blood cells (RBC), plasma and/or cerebrospinal fluid (CSF) between patients with sporadic amyotrophic lateral sclerosis (SALS), familial ALS (FALS) showing the Leu126Ser mutation in the Cu, Zn-SOD gene and controls. In patients with FALS or SALS, concentrations of hydroxyl radical in blood and ascorbate free radical and 8-OHdG in CSF were higher than control group values, while SOD activities in RBC and CSF were lower. In contrast, Cu, Zn-SOD protein concentrations in RBC were low only in FALS patients. Concentrations of Cu in CSF of SALS patients were higher than in controls. Thus, the pathogenesis of increased oxidative stress differs between SALS patients and FALS patients with a mutant Leu126Ser SOD1 gene.

Cytokine upregulation in a murine model of familial amyotrophic lateral sclerosis

Although pronounced changes in astrocytes and microglia accompany the neuronal degeneration observed in a murine model of familial amyotrophic lateral sclerosis, the significance of non-neuronal cell contribution to the disease process remains unclear. Activated astrocytes and microglia are capable of secreting numerous cytokines, some of which may have potentially harmful effects on neuron survival. For this reason we wished to determine the expression pattern of various cytokines in the spinal cords of transgenic mice expressing a Cu–Zn superoxide dismutase mutation (Tgn G93A SOD1) by using semi-quantitative RT–PCR. Three different patterns of cytokine expression were observed in G93A SOD1 transgenic mice. For most cytokines, we were unable to detect mRNA expression in Tgn G93A SOD1 mouse spinal cords at any age, yet message was readily detected in spleen or activated splenocytes. A second pattern, typified by TNF-α, was characterized by mRNA expression prior to the onset of motor deficits and increasing until the terminal stages of the disease. For other cytokines, including TGF-β1 and M-CSF, mRNA expression was detected in young presymptomatic Tgn G93A SOD1 mice (as well as wild-type and transgenic mice expressing wild-type SOD1 (Tgn SOD1)), with upregulation later occurring only in G93A SOD1 transgenic mice. These results indicate a temporal correlation between the expression of certain cytokines and the onset of motor dysfunction in Tgn G93A SOD1 mice and suggest a potential role for these molecules in the disease.

Effects of an Inhibitor of Poly(ADP-Ribose) Polymerase, Desmethylselegiline, Trientine, and Lipoic Acid in Transgenic ALS Mice

The development of transgenic mouse models of amyotrophic lateral sclerosis (ALS) allows the testing of neuroprotective agents. We evaluated the effects of five agents in transgenic mice with the G93A Cu,Zn superoxide dismutase mutation. A novel inhibitor of poly(ADP-ribose) polymerase showed no effects on survival. Desmethylselegiline and CGP3466 are agents that exert antiapoptotic effects in vitro by preventing nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase. They had no significant effects on survival in the G93A mice. Trientine, a copper chelator, produced a modest significant increase in survival. Similarly administration of lipoic acid in the diet produced a significant improvement in survival. These results therefore provide evidence for potential therapeutic effects of copper chelators and lipoic acid in the treatment of ALS.

Superoxide dismutase and oxygen radical neurotoxicity.

Although reactive oxygen species are natural metabolic products, they can be toxic to cells and are implicated in some neurodegenerative disease. Cytosolic Cu, Zn superoxide dismutase normally defends against damage by reactive oxygen species; however, mutant forms of the enzyme might instead contribute to damage of motor neurons n some amyotrophic lateral sclerosis patients. Possible mechanisms of oxidative injury to neurons are discussed with reference to cytosolic Cu, Zn superoxide dismutase mutations and other factors which might enhance oxygen radical toxicity.

Correction

In the report "Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation" by M. E. Gurney et al. (17 June 1994, p. 1772)(1), a systematic, 10-fold error was made in calculating the dilutions of brain extract used for determinations of total brain superoxide dismutase (SOD) activity shown in column 6 of table 1 (p. 1774). Each value reported should have been reduced by that factor, for example, the total SOD activity reported for the G1 line should have been 4.26 ± 0.2 SOD (U)/total protein (μg), not 42.6 ± 2.1 U/μg, and so forth.

Applied Research in South Africa

In the report "Motor neuron degeneration in mice that express a human Cu, Zn super-oxide dismutase mutation" by M. E. Gurney et al. (17 June 1994, p. 1772)(1), a systematic, 10-fold error was made in calculating the dilutions of brain extract used for determinations of total brain superoxide dismutase (SOD) activity shown in column 6 of table 1 (p. 1774). Each value reported should have been reduced by that factor, for example, the total SOD activity reported for the G1 line should have been 4.26 +/- 0.2 SOD (U)/total protein (microg), not 42.6 +/- 2.1 U/microg, and so forth.

Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.

Mutations of human Cu,Zn superoxide dismutase (SOD) are found in about 20 percent of patients with familial amyotrophic lateral sclerosis (ALS). Expression of high levels of human SOD containing a substitution of glycine to alanine at position 93--a change that has little effect on enzyme activity--caused motor neuron disease in transgenic mice. The mice became paralyzed in one or more limbs as a result of motor neuron loss from the spinal cord and died by 5 to 6 months of age. The results show that dominant, gain-of-function mutations in SOD contribute to the pathogenesis of familial ALS.