Krabbe disease (KD), also known as globoid cell leukodystrophy, is an inherited demyelinating disease caused by the deficiency of lysosomal galactosylceramidase (GALC) activity. Most of the patients are characterized by early-onset cerebral demyelination with apoptotic oligodendrocyte (OL) death and die before 2 years of age. However, the mechanisms of molecular pathogenesis in the developing OLs before death and the exact causes of white matter degeneration remain largely unknown. We have recently reported that OLs of twitcher mouse, an authentic mouse model of KD, exhibit developmental defects and endogenous accumulation of psychosine (galactosylsphingosine), a cytotoxic lyso-derivative of galactosylceramide. Here, we show that attenuated expression of microRNA (miR)-219, a critical regulator of OL differentiation and myelination, mediates cellular pathogenesis of KD OLs. Expression and functional activity of miR-219 were repressed in developing twitcher mouse OLs. By using OL precursor cells (OPCs) isolated from the twitcher mouse brain, we show that exogenously supplemented miR-219 effectively rescued their cell-autonomous developmental defects and apoptotic death. miR-219 also reduced endogenous accumulation of psychosine in twitcher OLs. Collectively, these results highlight the role of the reduced miR-219 expression in KD pathogenesis and suggest that miR-219 has therapeutic potential for treating KD OL pathologies.

中文翻译：

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miR-219 表达的降低是 Krabbe 病小鼠模型中少突胶质细胞发病机制的基础

克拉伯病（KD）也称为球状细胞脑白质营养不良，是一种由溶酶体半乳糖神经酰胺酶（GALC）活性缺乏引起的遗传性脱髓鞘疾病。大多数患者的特点是早发性脑脱髓鞘，伴有凋亡的少突胶质细胞（OL）死亡，并在 2 岁前死亡。然而，在死亡前发育中的OLs的分子发病机制以及白质变性的确切原因仍然很大程度上未知。我们最近报道了 twitcher 小鼠的 OLs，一种真正的 KD 小鼠模型，表现出发育缺陷和精神素（半乳糖基鞘氨醇）的内源性积累，一种半乳糖神经酰胺的细胞毒性溶血衍生物。在这里，我们发现 microRNA (miR)-219（OL 分化和髓鞘形成的关键调节因子）的表达减弱，介导 KD OLs 的细胞发病机制。miR-219 的表达和功能活性在发育中的 twitcher 小鼠 OL 中受到抑制。通过使用从 titcher 小鼠大脑中分离出来的 OL 前体细胞 (OPCs)，我们证明外源性补充的 miR-219 有效地挽救了它们的细胞自主发育缺陷和凋亡性死亡。miR-219 还减少了 titcher OLs 中精神素的内源性积累。总的来说，这些结果突出了 miR-219 表达降低在 KD 发病机制中的作用，并表明 miR-219 具有治疗 KD OL 病理的治疗潜力。我们表明，外源补充的 miR-219 有效地挽救了它们的细胞自主发育缺陷和凋亡。miR-219 还减少了 titcher OLs 中精神素的内源性积累。总的来说，这些结果突出了 miR-219 表达降低在 KD 发病机制中的作用，并表明 miR-219 具有治疗 KD OL 病理的治疗潜力。我们表明，外源补充的 miR-219 有效地挽救了它们的细胞自主发育缺陷和凋亡。miR-219 还减少了 titcher OLs 中精神素的内源性积累。总的来说，这些结果突出了 miR-219 表达降低在 KD 发病机制中的作用，并表明 miR-219 具有治疗 KD OL 病理的治疗潜力。