Reduction in miR-219 expression underlies cellular pathogenesis of oligodendrocytes in a mouse model of Krabbe disease.
Reduction in miR-219 expression underlies cellular pathogenesis of oligodendrocytes in a mouse model of Krabbe disease.
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DOI：
10.1111/bpa.12951
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Enokido Y
中科院分区：
文献类型：
--
作者：
Inamura N;Go S;Watanabe T;Takase H;Takakura N;Nakayama A;Takebayashi H;Matsuda J;Enokido Y
克拉伯病（Krabbe disease，KD）又称球样细胞脑白质营养不良（globoid cell leukodystrophy），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。大多数患者的特征是早发性脑脱髓鞘伴凋亡性少突胶质细胞（OL）死亡，并在2岁之前死亡。然而，死亡前发育中的OL的分子发病机制和白色物质变性的确切原因仍不清楚。我们最近报道了ticker小鼠（KD的真实小鼠模型）的OL表现出发育缺陷和精神肽（半乳糖基鞘氨醇）（半乳糖基神经酰胺的细胞毒性溶血衍生物）的内源性蓄积。在这里，我们发现microRNA（miR）-219的表达减弱，这是OL分化和髓鞘形成的关键调节因子，介导了KD OL的细胞发病机制。在发育中的抽搐小鼠OL中，miR-219的表达和功能活性受到抑制。通过使用从抽搐小鼠脑中分离的OL前体细胞（OPC），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死亡。miR-219还减少了颤搐性OL中的内源性Psychosine积累。总的来说，这些结果突出了降低的miR-219表达在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。Krabbe病（KD），或称球样细胞脑白质营养不良，是一种常染色体隐性遗传的溶酶体贮积病，伴有进行性脱髓鞘和凋亡性OL死亡。在这项研究中，我们发现miR-219的表达和功能活性在twitch小鼠的少突胶质细胞（OL）中受到抑制，这是一种真实的KD小鼠模型，并且twitch OL中的细胞病理学变化通过外源性补充miR-219而得到拯救。
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. Krabbe disease (KD), or globoid cell leukodystrophy, is an autosomal recessive lysosomal storage disease with progressive demyelination and apoptotic OL death. In this study, we found that the expression and functional activity of miR‐219 are repressed in oligodendrocytes (OLs) of twitcher mice, an authentic mouse model of KD, and that cellular pathological changes in twitcher OLs are rescued by exogenous supplementation with miR‐219.
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影响因子：
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DOI：
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发表时间：
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影响因子：
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影响因子：
16.2
作者：
Dugas JC;Cuellar TL;Scholze A;Ason B;Ibrahim A;Emery B;Zamanian JL;Foo LC;McManus MT;Barres BA
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