Pathology of general proprioception in a canine disease model of amyotrophic lateral sclerosis

Some forms of amyotrophic lateral sclerosis (ALS) are associated with sequence variants in the superoxide dismutase 1 gene (SOD1). The mechanisms by which these variants contribute to ALS disease pathogenesis are poorly understood. Degenerative myelopathy (DM), a naturally occurring canine disease, shares similarities with some forms of SOD1-associated ALS, especially cases with sensory impairment. While motor pathway involvement in ALS has been extensively studied, sensory pathology has received comparatively less attention. To investigate whether pathology in the general proprioceptive pathway is associated with pelvic limb general proprioceptive ataxia, an early DM sign, we examined sensory system components of this pathway from Pembroke Welsh Corgis with early- and late-stage DM and age-matched controls. The disease was characterized by axonal pathology in the spinocerebellar tracts and the fasciculus gracilis, pronounced accumulation of SOD1-positive inclusions in nucleus thoracicus and dorsal root ganglia (DRG) neurons, and altered SOD1 immunolabeling in dorsal and ventral root axons and ensheathing myelin. Axonal pathology was also observed in a pelvic limb sensory nerve. These findings suggest that pathology in the proprioceptive sensory pathways may play a significant role in general proprioceptive ataxia in DM. Some dogs that were homozygous for the SOD1 risk allele did not develop clinical disease or the associated neuropathology, indicating that other factors in addition to the SOD1 mutation influence disease onset and progression.