Abstract
A subset of patients of amyotrophic lateral sclerosis (ALS) present with mutation of Cu/Zn superoxide dismutase 1 (SOD1), and such mutants caused an ALS- like disorder when expressed in rodents. These findings implicated SOD1 in ALS pathogenesis and made the transgenic animals a widely used ALS model. However, previous studies of these animals have focused largely on motor neuron damage. We report herein that the spinal cords of mice expressing a human SOD1 mutant (hSOD1-G93A), besides showing typical destruction of motor neurons and axons, exhibit significant damage in the sensory system, including Wallerian-like degeneration in axons of dorsal root and dorsal funiculus, and mitochondrial damage in dorsal root ganglia neurons. Thus, hSOD1-G93A mutation causes both motor and sensory neuropathies, and as such the disease developed in the transgenic mice very closely resembles human ALS.
Highlights
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a progressive and fatal neurodegenerative disease
The present study was performed in transgenic mice expressing a hSOD1 mutant where two adjacent nucleotides of exon 4/codon 93 of superoxide dismutase 1 (SOD1) were mutated resulting in replacement of glycine by alanine, which occurs in some familial ALS patients (Rosen et al, 1993)
These results confirm the presence of motor neuron degeneration in the hSOD1-G93A mice and are consistent with previous findings (Gurney et al, 1994; Feeney et al, 2001; Zang and Cheema, 2002)
Summary
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a progressive and fatal neurodegenerative disease. Many of the hSOD1 mutants retain the enzymatic activity, but expression of such a mutant caused apoptosis in cultured neural cells and ALS-like disorder in animals while expression of the wild-type hSOD1 was not harmful (Gurney et al, 1994; Rabizadeh et al, 1995; Tu et al, 1996), one study reported that expressing high levels of wild-type hSOD1 in mice was mildly toxic to motor neurons (Jaarsma et al, 2000) These and other similar studies have led to the widely held belief that SOD1 mutation plays a major role in the pathogenesis of at least some familial ALS in humans. Sensory im pairment was detected in a patient of familial ALS with a missense mutation (Gly93→Ser) in exon 4 of hSOD1 (Kawata et al, 1997)
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