Validation of DE50-MD dogs as a model for the cognitive and biochemical defects in the brain phenotype of Duchenne muscular dystrophy

Crawford, Abbe; Hildyard, John; Rushing, Sophie; Wells, Dominic; Diez Leon, Maria; Piercy, Richard

Abstract

Duchenne muscular dystrophy (DMD), a fatal musculoskeletal disorder, is associated with neurodevelopmental problems and cognitive impairment caused by dystrophin deficiency in the brain. Dog models of DMD represent key translational tools to study dystrophin biology and to develop novel therapeutics, however, characterization of dystrophin expression and function in the canine brain is lacking. We have studied the DE50-MD canine model of DMD that has a missense mutation in the donor splice site of exon 50. Using a battery of cognitive tests, we have detected a neurocognitive phenotype in DE50-MD dogs including reduced attentiveness, problem-solving and exploration of novel objects compared to age-matched controls. Through a combination of qPCR, RNAScope in situ hybridization, capillary immunoelectrophoresis and immunolabelling we show that regional dystrophin expression in the adult canine brain reflects that of humans, and that the DE50-MD canine model of DMD lacks full length dystrophin (Dp427) protein expression but retains expression of the two shorter brain-expressed isoforms, Dp140 and Dp71. Thus, the DE50-MD dog is a translationally-relevant pre-clinical model to study the consequences of Dp427 deficiency in the brain and to develop therapeutic strategies for the neurological sequelae of DMD.

Citation

Crawford, A., Hildyard, J., Rushing, S., Wells, D., Diez Leon, M., & Piercy, R. (in press). Validation of DE50-MD dogs as a model for the cognitive and biochemical defects in the brain phenotype of Duchenne muscular dystrophy. eLife, https://doi.org/10.1242/dmm.049291

• Journal Article Type: Article
• Acceptance Date: Dec 21, 2021
• Online Publication Date: Jan 12, 2022
• Deposit Date: Nov 2, 2021
• Publicly Available Date: Feb 4, 2022
• Journal: eLife
• Electronic ISSN: 2050-084X
• Publisher: eLife Sciences Publications
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1242/dmm.049291
• Public URL: https://rvc-repository.worktribe.com/output/1549537