Assessment of metal concentrations in the SOD1\u3csup\u3eG93A\u3c/sup\u3e mouse model of amyotrophic lateral sclerosis and its potential role in muscular denervation, with particular focus on muscle tissue

Background: Amyotrophic lateral sclerosis (ALS) is among the most common of the motor neuron diseases, and arguably the most devastating. During the course of this fatal neurodegenerative disorder, motor neurons undergo progressive degeneration. The currently best-understood animal models of ALS are based on the over-expression of mutant isoforms of Cu/Zn superoxide dismutase 1 (SOD1); these indicate that there is a perturbation in metal homeostasis with disease progression. Copper metabolism in particular is affected in the central nervous system (CNS) and muscle tissue. Methods: This present study assessed previously published and newly gathered concentrations of transition metals (Cu, Zn, Fe and Se) in CNS (brain and spinal cord) and non-CNS (liver, intestine, heart and muscle) tissues from transgenic mice over-expressing the G93A mutant SOD1 isoform (SOD1 G93A), transgenic mice over-expressing wildtype SOD1 (SOD1WT) and non-transgenic controls. Results: Cu accumulates in non-CNS tissues at pre-symptomatic stages in SOD1G93A tissues. This accumulation represents a potentially pathological feature that cannot solely be explained by the over-expression of mSOD1. As a result of the lack of Cu uptake into the CNS there may be a deficiency of Cu for the over-expressed mutant SOD1 in these tissues. Elevated Cu concentrations in muscle tissue also preceded the onset of symptoms and were found to be pathological and not be the result of SOD1 over-expression. Conclusions: It is hypothesized that the observed Cu accumulations may represent a pathologic feature of ALS, which may actively contribute to axonal retraction leading to muscular denervation, and possibly significantly contributing to disease pathology. Therefore, it is proposed that the toxic-gain-of-function and dying-back hypotheses to explain the molecular drivers of ALS may not be separate, individual processes; rather our data suggests that they are parallel processes

Longitudinal assessment of metal concentrations and copper isotope ratios in the G93A SOD1 mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease, which involves progressive motor neuron degeneration in the central nervous system (CNS). The G93A SOD1 mouse model simulates one of the most common causes of familial ALS through the overexpression of a mutated form of the human gene encoding copper/zinc superoxide dismutase (SOD1). Transition metals, particularly Cu and Zn, have been shown to behave abnormally in the disease context and have been hypothesized to contribute to and potentially trigger the disease. In this study, concentrations of Cu, Zn and Fe, as well as Cu isotope ratios were assessed in keystone tissues of ALS, including the brain, spinal cord, muscle and whole blood, from transgenic mutant SOD1G93A mice and non-transgenic controls. While no consistent Cu isotope signal was found to be related to the disease state, concentrations of Cu, Zn and Fe were significantly elevated in muscle tissue of the transgenic mice, even at pre-symptomatic time points. In brain and muscle tissue, in both animal groups, a time-dependent Cu isotope signal was observed. We hypothesize that the early and significant elevation in metal concentration in muscle tissue from SOD1 transgenic mice could facilitate the development of ALS, without affecting the overall signal from well-buffered CNS tissues. Ageing may be recorded isotopically as a shift from a neonatal Cu pool as inherited from the mother, through dietary Cu and recycling processes

Assessment of metal concentrations in the SOD1\u3csup\u3eG93A\u3c/sup\u3e mouse model of amyotrophic lateral sclerosis and its potential role in muscular denervation, with particular focus on muscle tissue

Background: Amyotrophic lateral sclerosis (ALS) is among the most common of the motor neuron diseases, and arguably the most devastating. During the course of this fatal neurodegenerative disorder, motor neurons undergo progressive degeneration. The currently best-understood animal models of ALS are based on the over-expression of mutant isoforms of Cu/Zn superoxide dismutase 1 (SOD1); these indicate that there is a perturbation in metal homeostasis with disease progression. Copper metabolism in particular is affected in the central nervous system (CNS) and muscle tissue. Methods: This present study assessed previously published and newly gathered concentrations of transition metals (Cu, Zn, Fe and Se) in CNS (brain and spinal cord) and non-CNS (liver, intestine, heart and muscle) tissues from transgenic mice over-expressing the G93A mutant SOD1 isoform (SOD1 G93A), transgenic mice over-expressing wildtype SOD1 (SOD1WT) and non-transgenic controls. Results: Cu accumulates in non-CNS tissues at pre-symptomatic stages in SOD1G93A tissues. This accumulation represents a potentially pathological feature that cannot solely be explained by the over-expression of mSOD1. As a result of the lack of Cu uptake into the CNS there may be a deficiency of Cu for the over-expressed mutant SOD1 in these tissues. Elevated Cu concentrations in muscle tissue also preceded the onset of symptoms and were found to be pathological and not be the result of SOD1 over-expression. Conclusions: It is hypothesized that the observed Cu accumulations may represent a pathologic feature of ALS, which may actively contribute to axonal retraction leading to muscular denervation, and possibly significantly contributing to disease pathology. Therefore, it is proposed that the toxic-gain-of-function and dying-back hypotheses to explain the molecular drivers of ALS may not be separate, individual processes; rather our data suggests that they are parallel processes