Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by degeneration and loss of motor neurons in the spinal cord, brainstem and motor cortex. Up to 10% of ALS cases are inherited (familial, fALS) and associated with mutations, frequently in the superoxide dismutase 1 (SOD1) gene. Rodent transgenic models of ALS are often used to elucidate a complex pathogenesis of this disease. Of importance, both ALS patients and animals carrying mutated human SOD1 gene show symptoms of oxidative stress and iron metabolism misregulation. The aim of our study was to characterize changes in iron metabolism in one of the most commonly used models of ALS – transgenic mice overexpressing human mutated SOD1G93A gene. We analyzed the expression of iron-related genes in asymptomatic, 2-month-old and symptomatic, 4-month-old SOD1G93A mice. In parallel, respective age-matched mice overexpressing human non-mutated SOD1 transgene and control mice were analyzed. We demonstrate that the overexpression of both SOD1 and SOD1G93A genes account for a substantial increase in SOD1 protein levels and activity in selected tissues and that not all the changes in iron metabolism genes expression are specific for the overexpression of the mutated form of SOD1.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most widespread motor neuron disease
We found that in spinal cord, M. oblongata (Figure 1B), liver and kidney (Figure 1C) of the transgenic superoxide dismutase 1 (SOD1) mice SOD1 protein was expressed at a higher level than in the corresponding tissues of the ALS mice these differences did not reach statistical significance
Among antioxidant enzymes the family of ubiquitous superoxide dismutase (SOD) deserves special attention because the reaction catalyzed by SODs converts one reactive oxygen species (ROS) (O·2−) to another (H2O2), and these enzymes play a subtle role in the regulation of ROS balance (Zelko et al, 2002)
Summary
Amyotrophic lateral sclerosis (ALS) is the most widespread motor neuron disease. It is characterized by a progressive and selective degeneration of neurons in motor cortex and lower motor neurons projecting from the brainstem and spinal cord. The evidence of the involvement of oxidative stress in ALS pathology originates from studies on ALS patients (Carri et al, 2003) as well as from experiments on rodent models of this disease, which are in vast majority transgenic mice that overexpress mutated human SOD1 gene (Turner and Talbot, 2008). In general these mouse models recapitulate human disease, some critical differences exist between the animal and human pathology. It is not surprising that the toxicity induced by oxidative stress has been reported in both, SOD1 null mice (Reaume et al, 1996) and in mice overexpressing human wild-type SOD1 gene (Lee et al, 2001)
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