Elsevier

Neuroscience

Volume 130, Issue 4, 2005, Pages 897-910
Neuroscience

The effect of peripheral nerve injury on disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis

https://doi.org/10.1016/j.neuroscience.2004.09.069Get rights and content

Abstract

Around 20% of familial cases of amyotrophic lateral sclerosis have been shown to carry mutations in Cu/Zn superoxide dismutase 1 (Cu/Zn SOD1). Transgenic mice over-expressing human mutant SOD1 genes have been developed and in this study we examined the effect of nerve injury on disease progression in these mice. Firstly, disease progression in uninjured mice was characterised using physiological methods. Muscle force, contractile characteristics and motor unit survival was established at 90 days, an early symptomatic stage and also at the end-stage of the disease, at 130 days. In addition, muscle histochemistry was examined and the extent of motoneuron survival established morphologically. By 90 days of age, there is a significant reduction in muscle force, and nearly 40% of motoneurons within the sciatic motor pool have already died. By 130 days, the muscles are significantly weaker, and there is a dramatic change in the phenotype of extensor digitorum longus (EDL), which changes from a fast fatigable muscle, to a fatigue resistant muscle with a high oxidative capacity. By this stage of the disease, only 40% of motor units in EDL survive, with only 29% of motoneurons surviving within the sciatic motor pool. Following injury to the sciatic nerve in SOD1(G93A) mice, there is an acceleration in disease progression so that 90 day old mice show deficits that are only seen at the end stage in uninjured SOD1(G93A) mice. It is therefore possible that mutant SOD1 toxicity increases the vulnerability of motoneurons and muscles to stressful stimuli such as nerve injury.

Section snippets

Experimental procedures

Transgenic mice with a G93A mutation of the human SOD1 gene (TgN[SOD1-G93A]1Gur; Jackson Laboratory, Bar Harbor, ME, USA), were maintained by breeding male heterozygous carriers to female B6SJLF1 hybrids. The SOD1(G93A) transgenic mice were identified using polymerase chain reaction amplification of the transgene from genomic DNA. Male mice were used in these experiments and all experimental procedures were carried out under Licence from the Home Office in accordance with The Animals

Assessment of disease progression in SOD1(G93A) mice

The decline in motor function and extent of motoneuron degeneration in SOD1(G93A) mice was assessed at the approximate time of disease onset, at 90 days of age, when there was behavioural signs of motor deficits such hindlimb tremor, and also at the end-stage of the disease when the animals were 130 days old.

Discussion

In this study we examined disease progression in a transgenic mouse model of familial ALS and assessed the effect of inducing motoneurons to grow, by injury to their peripheral nerve, on motoneuron survival and muscle function.

Acknowledgments

This work was supported by the Brain Research Trust (BRT). P.S. was in receipt of an MRC Studentship and L.G. is the Graham Watts Senior Research Fellow, funded by the BRT.

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