Dystrophin deficiency leads to dysfunctional glutamate clearance in iPSC derived astrocytes

• Published in: Translational psychiatry Vol. 9; no. 1; pp. 200 - 21
• Main Authors: Patel, Abdulsamie M., Wierda, Keimpe, Thorrez, Lieven, van Putten, Maaike, De Smedt, Jonathan, Ribeiro, Luis, Tricot, Tine, Gajjar, Madhavsai, Duelen, Robin, Van Damme, Philip, De Waele, Liesbeth, Goemans, Nathalie, Tanganyika-de Winter, Christa, Costamagna, Domiziana, Aartsma-Rus, Annemieke, van Duyvenvoorde, Hermine, Sampaolesi, Maurilio, Buyse, Gunnar M., Verfaillie, Catherine M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.08.2019; Nature Publishing Group
• Subjects: 13/100; 13/106; 13/31; 14/19; 14/56; 38/39; 38/77; 631/532; 692/699/476/1373; Astrocytes - cytology; Astrocytes - metabolism; Behavioral Sciences; Biological Psychology; Calcium - metabolism; Cytoskeleton - metabolism; Defects; Dystrophin - genetics; Dystrophin - metabolism; Glutamic Acid - metabolism; Homeostasis; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Male; Medicine; Medicine & Public Health; Muscular Dystrophy, Duchenne - genetics; Muscular Dystrophy, Duchenne - metabolism; Mutation; Neuronal Outgrowth - physiology; Neurons - cytology; Neurons - metabolism; Neurosciences; Nitric Oxide - metabolism; Pharmacotherapy; Psychiatry
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/s41398-019-0535-1

Duchenne muscular dystrophy (DMD) results, beside muscle degeneration in cognitive defects. As neuronal function is supported by astrocytes, which express dystrophin, we hypothesized that loss of dystrophin from DMD astrocytes might contribute to these cognitive defects. We generated cortical neuronal and astrocytic progeny from induced pluripotent stem cells (PSC) from six DMD subjects carrying different mutations and several unaffected PSC lines. DMD astrocytes displayed cytoskeletal abnormalities, defects in Ca +2 homeostasis and nitric oxide signaling. In addition, defects in glutamate clearance were identified in DMD PSC-derived astrocytes; these deficits were related to a decreased neurite outgrowth and hyperexcitability of neurons derived from healthy PSC. Read-through molecule restored dystrophin expression in DMD PSC-derived astrocytes harboring a premature stop codon mutation, corrected the defective astrocyte glutamate clearance and prevented associated neurotoxicity. We propose a role for dystrophin deficiency in defective astroglial glutamate homeostasis which initiates defects in neuronal development.