Lithium Improves Cell Viability in Psychosine-Treated MO3.13 Human Oligodendrocyte Cell Line Via Autophagy Activation
Lithium Improves Cell Viability in Psychosine-Treated MO3.13 Human Oligodendrocyte Cell Line Via Autophagy Activation
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DOI：
10.1002/jnr.23910
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发表时间：
2016-11-01
影响因子：
4.2
通讯作者：
Cecchini, Marco
中科院分区：
文献类型：
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作者：
Del Grosso, Ambra;Antonini, Sara;Cecchini, Marco
球状细胞白质营养不良症(GLD)是一种少见的、进展迅速的儿童脑白质营养不良症，由溶酶体酶半乳糖神经酰胺酶(GALC)缺陷引发，其特征是半乳糖神经鞘氨醇(半乳糖；PSY)在神经系统积聚。PSY是一种细胞毒性鞘磷脂，可导致少突胶质细胞和雪旺细胞的广泛变性，导致脱髓鞘。在这里，我们报道了PSY处理的人少突胶质细胞系MO3.13的自噬以及利用Li作为自噬调节剂来挽救细胞活力。我们证明PSY在自噬小体和自溶酶体形成以及LC3-II表达水平上引起自噬通量的上调。我们发现，用临床上用于治疗双相情感障碍的药物LI进行预处理，可以进一步刺激自噬，提高细胞对PSY的耐受性。这种锂的保护作用被发现与减少PSY诱导的氧化应激无关，也可能不是因为减少了PSY的积累。这些数据提供了在PSY诱导的毒性过程中激活的细胞内通路的新信息，并表明自噬途径有望成为改善GLD表型的新的治疗靶点。(C)2016威利期刊公司。
Globoid cell leukodystrophy (GLD) is a rare, rapidly progressing childhood leukodystrophy triggered by deficit of the lysosomal enzyme galactosylceramidase (GALC) and characterized by the accumulation of galactosylsphingosine (psychosine; PSY) in the nervous system. PSY is a cytotoxic sphingolipid, which leads to widespread degeneration of oligodendrocytes and Schwann cells, causing demyelination. Here we report on autophagy in the human oligodendrocyte cell line MO3.13 treated with PSY and exploitation of Li as an autophagy modulator to rescue cell viability. We demonstrate that PSY causes upregulation of the autophagic flux at the level of autophagosome and autolysosome formation and LC3-II expression. We show that pretreatment with Li, a drug clinically used to treat bipolar disorders, can further stimulate autophagy, improving cell tolerance to PSY. This Li protective effect is found not to be linked to reduction of PSY-induced oxidative stress and might not stem from a reduction of PSY accumulation. These data provide novel information on the intracellular pathways activated during PSY-induced toxicity and suggest the autophagy pathway as a promising novel therapeutic target for ameliorating the GLD phenotype. (C) 2016 Wiley Periodicals, Inc.