a disease model for amyotrophic lateral sclerosis

Dogs homozygous for missense mutations in superoxide dismutase 1 (SOD1) develop a late-onset neuromuscular disorder called degenerative myelopathy (DM) that has many similarities to amyotrophic lateral sclerosis (ALS). Both disorders are characterized by widespread progressive declines in motor and sensory functions accompanied by atrophic changes in the ascending and descending spinal cord tracts. Additionally, some forms of ALS are also associated with SOD1 mutations. In end-stage ALS, death usually occurs as a result of respiratory failure due to severe functional impairment of respiratory muscles. The mechanisms that lead to this loss of function are not known. Dogs with DM are euthanized at all stages of disease progression providing an opportunity to characterize the onset and progression of any pathological changes in the respiratory muscles that may precede respiratory failure. To characterize such potential disease-related pathology we evaluated intercostal muscles from Boxer and Pembroke Welsh Corgi (PWC) dogs that were euthanized at various stages of DM disease progression. DM was found to result in intercostal muscle atrophy, fibrosis, and an alteration in muscle fiber type composition. This pathology was not accompanied by retraction of the motor axon terminals from the muscle acetylcholine receptor complexes, suggesting that the muscle atrophy did not result from physical denervation. To determine if other components of the thoracic motor unit (cell body, axon, and myofibers) also demonstrated morphological changes consistent with dysfunction, histopathologic and morphometric analyses were conducted on thoracic spinal motor neurons (MNs) and in motor root axons from DM-dogs. Because sensory dysfunction is known to occur in DM, dorsal root ganglia (DRG), and sensory root axons were also analyzed. No alterations in MNs, or motor root axons were observed in either breed. However, advanced stage PWCs exhibited significant losses of sensory root axons, and numerous DRG sensory neurons displayed evidenceIncludes bibliographical references (pages 89-101)