The role of dystrophin isoforms and interactors in the brain

Dystrophin is a protein crucial for maintaining the structural integrity of skeletal muscle. So far, the attention was focused on the role of dystrophin in muscle in view of the devastating progression of weakness and early death that characterises 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, Purkinje cells, cerebellar granule cells, 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, and the associated clinical complications. We focus on studies investigating protein interactions with dystrophin in the past 30 years, at a biochemical level. In essence, brain's dystrophin landscape is a thrilling exploration of diversity, challenging preconceptions and opening new avenues for understanding the central nervous system physiology. It also holds potential therapeutic implications for neurological complications in which brain dystrophin deficiency is involved. By revealing the molecular complexities related to dystrophin, this review paves the way for future investigations and therapeutic interventions for this central nervous system aspect of Duchenne muscular dystrophy.