Characterization of thoracic motor and sensory neurons and spinal nerve roots in canine degenerative myelopathy, a potential disease model of amyotrophic lateral sclerosis

Abstract

Canine Degenerative Myelopathy (DM) is a progressive adult-onset multisystem degenerative disease with many features in common with amyotrophic lateral sclerosis (ALS). As with some forms of ALS, DM is associated with mutations in superoxide dismutase 1 (SOD1). Clinical signs include general proprioceptive ataxia and spastic upper motor neuron paresis in pelvic limbs, which progress to flaccid tetraplegia and dysphagia. The purpose of this study was to characterize DM as a potential disease model for ALS. We previously reported that intercostal muscle atrophy develops in dogs with advanced stage DM. To determine if other components of the thoracic motor unit (MU) also demonstrated morphological changes consistent with dysfunction, histopathologic and morphometric analyses were conducted on thoracic spinal motor neurons (MN) and dorsal root ganglia (DRG), and in motor and sensory nerve root axons from DM-affected Boxers and Pembroke Welsh Corgis (PWCs). 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 evidence of degeneration. These results indicate that intercostal muscle atrophy in DM is not preceded by physical loss of the motor neurons innervating these muscles, or of their axons. Axonal loss in thoracic sensory roots and sensory nerve death suggest sensory involvement may play an important role in DM disease progression. Further analysis of the mechanisms responsible for these morphological findings would aid in the development of therapeutic intervention for DM and some forms of ALS.

Canine degenerative myelopathy: a model of human amyotrophic lateral sclerosis

“…Sensory involvement may thus play an important role in CDM disease progression. The loss of thoracic sensory root axons and the evidence of degeneration in DRG neurons are consistent with the report of CDM-associated sensory nerve pathology (Griffiths and Duncan, 1975), although the degenerative changes that Morgan et al (2014) observed in the DRG neurons were more profound than the mild central chromatolysis previously reported. Although clinical signs of CDM and ALS are primarily associated with motor dysfunction, sensory deficits are also known to occur as part of the clinical spectrum of both diseases (Averill, 1973;Dyck et al, 1975;Mulder et al, 1983;Andersen et al, 1995Andersen et al, , 1996Isaacs et al, 2007;Pugdahl et al, 2007;Coates and Wininger, 2010).…”

“…A histopathological examination revealed the loss of large myelinated nerve fibers as well as clusters of presumptive regenerating fibers in common peroneal nerves (Morgan et al, 2014). Degeneration of intramuscular nerve branches, as evidenced by myelin ovoids and nerve fiber loss, has been observed in all affected Boxers at the later disease stage, consistent with a dyingback polyneuropathy.…”

“…In a subsequent study, Morgan et al (2014) also examined the thoracic sensory neurons and spinal nerve roots in PWCs in the advanced stage of disease. They found a significant loss of sensory root axons and degenerative changes in the sensory neurons of numerous dorsal root ganglia (DRG) (Fig.…”

“…Dorsal root ganglia neurons from grade 4 Pembroke Welsh Corgis (D) contained numerous cells with condensed cytoplasm (arrowhead) and severely pyknotic nuclei (arrow) that were not present in the dorsal root ganglia neurons from age-matched control dogs (arrowhead and arrow in C denote cytoplasm and nucleus of normal neuron for comparison). Reproduced with permission fromMorgan et al (2014);…”

Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy

“…A presumptive clinical diagnosis is made by ruling out potential causes of compressive myelopathy; however, confirmation requires histopathological examination of the spinal cord (16). The pathological features of DM are similar to the pathological features of ALS (17)(18)(19)(20)(21)(22). DM has been confirmed in over 24 breeds (16,23) and presumptively reported in another nine breeds (16).…”