Amyotrophic lateral sclerosis (ALS) is a motor neuron-specific neurodegenerative disorder. Superoxide dismutase 1 (SOD1) gene mutations have been known to cause approximately 20% of familial ALS cases. In dogs, SOD1 mutations (E40K and T18S) have been linked to degenerative myelopathy (DM). In the present study, we described a detailed clinical course of DM, histopathological characteristics of affected spinal cords, and biochemical properties of E40K proteins to provide a better understanding of this novel canine model of ALS.
The clinical symptoms in dogs were characterized by a late-onset, progressive and fatal spinal cord disorder. The early signs were pelvic general proprioceptive ataxia and upper motor neuron paraparesis. The clinical signs progressed to lower motor neuron quadriplegia, and eventually respiratory failure. The histopathological features of postmortem spinal tissues were axonal loss and demyelination. Immunohistochemistry with an E40K-specific antibody revealed accumulation of mutant SOD1 species in neuronal cell bodies. Biochemical analyses of E40K proteins demonstrated their reduced detergent solubility and tendency to form high molecular weight complexes.
A variety of treatments have been found effective in transgenic mice expressing human mutant SOD1, but few treatments have proven successful in clinical trials. Rodent ALS models are likely to possess very high levels of mutant SOD1 expression, which may induce pathologic processes distinct from those affecting ALS patients. Dogs with DM, on the other hand, result from a spontaneous SOD1 mutation and may mirror more closely human ALS.