Tetorou Konstantina, Aghaeipour Artadokht, Singh Simran, Morgan Jennifer E, Muntoni Francesco
Developmental Neurosciences Department, Dubowitz Neuromuscular Centre, University College London, Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
Developmental Neurosciences Department, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, London WC1N 1EH, UK.
Brain. 2025 Apr 3;148(4):1081-1098. doi: 10.1093/brain/awae384.
Dystrophin is a protein crucial for maintaining the structural integrity of skeletal muscle. So far, attention has been focused on the role of dystrophin in muscle, in view of the devastating progression of weakness and early death that characterizes Duchenne muscular dystrophy. However, in the last few years, the role of shorter dystrophin isoforms, including development and adult expression-specific mechanisms, has been a greater focus. Within the cerebral landscape, various cell types, such as glia, oligodendrocytes and Purkinje, cerebellar granule and vascular-associated cells express a spectrum of dystrophin isoforms, including Dp427, Dp140, Dp71 and Dp40. The interaction of these isoforms with a multitude of proteins suggests their involvement in neurotransmission, influencing several circuit functions. This review presents the intricate interactions among dystrophin isoforms and diverse protein complexes across different cell types and brain regions, as well as the associated clinical complications. We focus on studies investigating protein interactions with dystrophin in the past 30 years at a biochemical level. In essence, the brain's dystrophin landscape is a thrilling exploration of diversity, challenging preconceptions and opening new avenues for understanding CNS physiology. It also holds potential therapeutic implications for neurological complications involving brain dystrophin deficiency. By revealing the molecular complexities related to dystrophin, this review paves the way for future investigations and therapeutic interventions for this CNS aspect of Duchenne muscular dystrophy.
抗肌萎缩蛋白是一种对维持骨骼肌结构完整性至关重要的蛋白质。到目前为止，鉴于杜氏肌营养不良症所具有的毁灭性的肌无力进展和早期死亡特征，人们一直将注意力集中在抗肌萎缩蛋白在肌肉中的作用上。然而，在过去几年中，较短的抗肌萎缩蛋白亚型的作用，包括其发育和成年期表达特异性机制，受到了更多关注。在大脑领域，各种细胞类型，如神经胶质细胞、少突胶质细胞以及浦肯野细胞、小脑颗粒细胞和血管相关细胞，都表达一系列抗肌萎缩蛋白亚型，包括Dp427、Dp140、Dp71和Dp40。这些亚型与多种蛋白质的相互作用表明它们参与神经传递，影响多种神经回路功能。本综述介绍了抗肌萎缩蛋白亚型与不同细胞类型和脑区中多种蛋白质复合物之间的复杂相互作用，以及相关的临床并发症。我们重点关注过去30年在生化水平上研究蛋白质与抗肌萎缩蛋白相互作用的研究。从本质上讲，大脑中的抗肌萎缩蛋白情况是一次对多样性的激动人心的探索，挑战了先入之见，并为理解中枢神经系统生理学开辟了新途径。它对涉及脑抗肌萎缩蛋白缺乏的神经并发症也具有潜在的治疗意义。通过揭示与抗肌萎缩蛋白相关的分子复杂性，本综述为杜氏肌营养不良症中枢神经系统方面的未来研究和治疗干预铺平了道路。
