Journal
DISEASE MODELS & MECHANISMS
Volume 15, Issue 3, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.049291
Keywords
Duchenne muscular dystrophy; Brain; Cognitive; Dog; Animal model
Categories
Funding
- Wellcome Trust [101550/Z/13/Z]
- Academy of Medical Sciences
- Wellcome Trust
- Medical Research Council
- British Heart Foundation
- Versus Arthritis
- Diabetes UK
- British Thoracic Society
- Association of Physicians of Great Britain and Ireland [SGL020\1081]
- Animal Care Trust at the Royal Veterinary College [11851718]
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This study found a neurocognitive phenotype in the DE50-MD dog model of DMD and characterized the expression of dystrophin in the canine brain using various methods. The findings suggest that the DE50-MD dog is a valuable translational model for studying the consequences of dystrophin deficiency in the brain and developing therapeutic strategies for DMD neurologic sequelae.
Duchenne muscular dystrophy (DMD), a fatal musculoskeletal disease, is associated with neurodevelopmental disorders and cognitive impairment caused by brain dystrophin deficiency. Dog models of DMD represent key translational tools to study dystrophin biology and to develop novel therapeutics. However, characterisation of dystrophin expression and function in the canine brain is lacking. We 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 detected a neurocognitive phenotype in DE50MD dogs, including reduced attention, problem solving and exploration of novel objects. Through a combination of capillary immunoelectrophoresis, immunolabelling, quantitative PCR and RNAScope in situ hybridisation, we show that regional dystrophin expression in the adult canine brain reflects that of humans, and that the DE50-MD dog lacks full-length dystrophin (Dp427) protein expression but retains expression of the two shorter brainexpressed 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.
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