Establishing the neuropathologic and molecular features of a spontaneous canine model of peripheral neuropathy

PROJECT SUMMARY/ABSTRACT Hereditary peripheral neuropathies (HPNs) are common disorders that involve degeneration of nerves in the peripheral nervous system. Common clinical signs include progressive muscle weakness, foot deformities, and sensory deficits. There are no FDA-approved treatments for HPNs. Spontaneous large animal models of neurodegenerative diseases have consistently proven valuable. Domestic dogs are excellent models of human disease because they cohabitate with humans, their genomic features are highly conserved with humans, their peripheral nerves have similar metabolic requirements to humans, and they have an aging phenotype that mimics humans. Late-onset peripheral neuropathy (LPN), a spontaneous degenerative HPN that is common in Labrador Retrievers, is poised to be an excellent spontaneous canine model for human axonal HPNs. To initiate the use of this model for fundamental research and pre-clinical trials, further investigation into its pathologic basis is needed. Thus, we propose to further characterize the neuropathologic and molecular features of LPN to establish it as a spontaneous canine model for human axonal HPNs. The current known neuropathologic features of Labrador LPN align with human axonal HPNs, although the neuromuscular junction is a key feature that has not yet been researched. In Aim 1a, we will investigate the neuropathologic architecture of the neuromuscular junction and corresponding peripheral nerves in LPN-affected Labradors and controls. We have identified a novel variant in a robust candidate gene that strongly associates with LPN-affected Labradors, but the mechanism by which this variant contributes to axonal degeneration is unknown. In Aim 1b, we will evaluate the functional effect of this variant on its gene and protein product. Uncovering the molecular mechanisms contributing to axon degeneration in Labrador LPN is essential in identifying overlapping treatment targets between Labrador LPN and human axonal HPNs. In Aim 2, we will identify abnormalities associated with Labrador LPN using a novel induced-motor neuron model. The training plan proposed under this award involves extensive individualized training in research techniques, conceptual knowledge, scientific communication, responsible conduct of research, collaborative science, clinical neurological and surgical skills, and professional development. My sponsors’ laboratories, the Comparative Biomedical Sciences graduate program, the dual DVM/PhD program, and the University of Wisconsin-Madison School of Veterinary Medicine will provide me with an outstanding opportunity to undertake research and training that will form a solid foundation towards my goal of becoming an independent veterinary clinician scientist. The work performed under this award will contribute to the establishment of Labrador LPN as a spontaneous canine model for human axonal HPNs. In the future, this model will be used as the critical link to human clinical trials, serving to assist in the discovery of a treatment for this disorder.