Abstract
Cognitive deficit has been identified in one third of patients affected by Duchenne Muscular Dystrophy, primarily attributed to loss of the short Dp71 dystrophin, the major brain dystrophin isoform. In this study, we investigated for the first time the Dp71 and Dp71-associated proteins cellular localization and expression in human neurons obtained by differentiation from induced pluripotent stem cell line of a patient affected by cognitive impairment. We found structural and molecular alterations in both pluripotent stem cell and derived neurons, reduced Dp71 expression, and a Ca2+ cytoplasmic overload in neurons coupled with increased expression of the SERCA2 pump in the dystrophic neurons. These results suggest that the reduction of Dp71 protein in the Duchenne muscular dystrophy neurons leads to alterations in SERCA2 and to elevated cytosolic Ca2+ concentration with consequent potential disruption of the dystrophin proteins and Dp71-associated proteins.
Highlights
Mutations in the dmd gene are responsible for the Duchenne muscular dystrophy (DMD) disease [1], in which muscular degeneration is associated with cognitive defects likely due to loss of the smallest product of the dmd gene, the Dp71 dystrophin isoform [2]
Morphometric analysis shows a meaningful reduction of Dp71, Water channel aquaporin-4 (AQP4), Dys, and βDG fluorescence intensity in DMD-Human-induced pluripotent stem cells (hiPSCs) compared to controls (Fig. 1r)
Real-time PCR experiments revealed a significant reduction in mRNA amount of Dp71, AQP4, Dys, and an increment of the messenger for DG in DMD-hiPSCs compared to control (Additional file 1: Figure S1)
Summary
Mutations in the dmd gene are responsible for the Duchenne muscular dystrophy (DMD) disease [1], in which muscular degeneration is associated with cognitive defects likely due to loss of the smallest product of the dmd gene, the Dp71 dystrophin isoform [2]. Dp71 is the most abundant dystrophin gene product in the adult brain [3, 4], and DMD patients with Dp71 partial ablation display severe mental retard with a reduction of the mean intelligence quotient (IQ) by about 1 standard deviation [5]. In the CNS, Dp71 is detected in neurons [6], but little is known about its function for no availability of DMD patient’s brain tissues. Differentiation of hiPSCs into neural cells provides a recent technology to generate living neurons genetically identical to the patients’ ones. Ruggieri et al Stem Cell Research & Therapy (2019) 10:29
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