Comparative Neuromuscular Diseases Laboratory, Department of Clinical Science and Services, Royal Veterinary College, London NW1 0TU, UK.
Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK.
Dis Model Mech. 2022 Mar 1;15(3). doi: 10.1242/dmm.049291. Epub 2022 Mar 2.
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 DE50-MD 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 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.
杜氏肌营养不良症（DMD）是一种致命的肌肉骨骼疾病，与神经发育障碍和大脑中肌营养不良蛋白缺乏引起的认知障碍有关。DMD 的犬模型是研究肌营养不良蛋白生物学和开发新疗法的重要转化工具。然而，犬脑中肌营养不良蛋白的表达和功能特征尚未得到研究。我们研究了 DE50-MD 犬模型，该模型在 50 号外显子的供体位点发生了错义突变。使用一系列认知测试，我们在 DE50-MD 犬中检测到了神经认知表型，包括注意力、解决问题和探索新物体的能力下降。通过毛细管免疫电泳、免疫标记、定量 PCR 和 RNAScope 原位杂交的组合，我们表明成年犬脑中的区域性肌营养不良蛋白表达反映了人类的表达，并且 DE50-MD 犬缺乏全长肌营养不良蛋白（Dp427）蛋白表达，但保留了两种较短的脑表达亚型，Dp140 和 Dp71 的表达。因此，DE50-MD 犬是一种具有转化意义的临床前模型，可用于研究大脑中 Dp427 缺乏的后果，并为 DMD 的神经后遗症开发治疗策略。
