Abstract
In addition to progressive muscular degeneration due to dystrophin mutations, 1/3 of Duchenne muscular dystrophy (DMD) patients present cognitive deficits. However, there is currently an incomplete understanding about the function of the multiple dystrophin isoforms in human brains. Here, we tested the hypothesis that dystrophin deficiency affects glial function in DMD and could therefore contribute to neural impairment. We investigated human dystrophin isoform expression with development and differentiation and response to damage in human astrocytes from control and induced pluripotent stem cells from DMD patients. In control cells, short dystrophin isoforms were up-regulated with development and their expression levels changed differently upon neuronal and astrocytic differentiation, as well as in 2-dimensional versus 3-dimensional astrocyte cultures. All DMD-astrocytes tested displayed altered morphology, proliferative activity and AQP4 expression. Furthermore, they did not show any morphological change in response to inflammatory stimuli and their number was significantly lower as compared to stimulated healthy astrocytes. Finally, DMD-astrocytes appeared to be more sensitive than controls to oxidative damage as shown by their increased cell death. Behavioral and metabolic defects in DMD-astrocytes were consistent with gene pathway dysregulation shared by lines with different mutations as demonstrated by bulk RNA-seq analysis. Together, our DMD model provides evidence for altered astrocyte function in DMD suggesting that defective astrocyte responses may contribute to neural impairment and might provide additional potential therapeutic targets.
Highlights
Duchenne Muscular dystrophy (DMD), a progressive neuromuscular disease that affects 1 in 3000–5000 male children, leads to loss of ambulation by the early teens and death by the 3-4th decade of life (Blake et al, 2002; Muntoni et al, 2003; Ricotti et al, 2016)
We have addressed some of these issues, firstly by analyzing changes in dystrophin isoforms in the human developing brain and upon differentiation of human neural stem cells into neurons and astrocytes, and secondly by testing the hypothesis that astrocytes derived from DMD
We show that all shorter dystrophin isoforms are up-regulated with normal development, and that whilst neurons express most isoforms, Dp71 is the main isoform expressed in astrocytes
Summary
Duchenne Muscular dystrophy (DMD), a progressive neuromuscular disease that affects 1 in 3000–5000 male children, leads to loss of ambulation by the early teens and death by the 3-4th decade of life (Blake et al, 2002; Muntoni et al, 2003; Ricotti et al, 2016). In addition to muscle wasting, and much less well understood, are the central nervous system comorbidities occurring in at least a third of DMD patients. These patients exhibit an IQ on average one standard deviation lower than the general population and suffer from a range of neuropsychiatric comorbidities including attention deficit hyperactivity disorder (ADHD) and autism (Pane et al, 2012; Ricotti et al, 2016; Wingeier et al, 2011). DMD is composed of 79 exons and its expression is regulated by different promoters with distinct tissue specificity It contains 3 promoter regions encoding full-length isoforms (Dp427) as well as at least 4 internal promoter regions encoding the shorter isoforms (Dp260, Dp140, Dp116 and Dp71/ Dp40). All these shorter isoforms with possibly the exception of Dp116 are transcribed in the central nervous system (CNS) but not in muscle (Waite et al, 2012)
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