Stem Cell Institute Leuven, Dept. of Development and Regeneration, KU Leuven, Leuven, Belgium.
Center for Brain & Disease Research, VIB, Leuven, Belgium.
Transl Psychiatry. 2019 Aug 21;9(1):200. 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 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.
杜氏肌营养不良症 (DMD) 除肌肉退化外，还会导致认知缺陷。由于星形胶质细胞支持神经元功能，而星形胶质细胞表达肌营养不良蛋白，因此我们假设 DMD 星形胶质细胞中肌营养不良蛋白的缺失可能导致这些认知缺陷。我们从六位携带不同突变的 DMD 受试者和几条未受影响的 PSC 系中诱导的多能干细胞 (PSC) 生成皮质神经元和星形胶质细胞祖细胞。DMD 星形胶质细胞显示细胞骨架异常、钙稳态和一氧化氮信号缺陷。此外，在源自 DMD PSC 的星形胶质细胞中鉴定出谷氨酸清除缺陷；这些缺陷与源自健康 PSC 的神经元的突起生长减少和过度兴奋有关。通读分子恢复了携带过早终止密码子突变的 DMD PSC 衍生星形胶质细胞中的肌营养不良蛋白表达，纠正了有缺陷的星形胶质细胞谷氨酸清除缺陷，并防止了相关的神经毒性。我们提出肌营养不良蛋白缺乏在星形胶质细胞谷氨酸稳态缺陷中起作用，从而引发神经元发育缺陷。
