Phosphatidic acid mediates demyelination in Lpin1 mutant mice
Phosphatidic acid mediates demyelination in Lpin1 mutant mice
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DOI：
10.1101/gad.1638008
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发表时间：
2008-06-15
影响因子：
10.5
通讯作者：
Chrast, Roman
中科院分区：
文献类型：
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作者：
Nadra, Karim;Charles, Anne-Sophie de Preux;Chrast, Roman
脂质在神经胶质细胞生物学的许多方面起着至关重要的作用，影响从髓鞘膜生物合成到轴胶质相互作用的过程。为了研究脂质代谢在髓鞘胶质细胞中的作用，我们在雪旺细胞中特异性地删除了Lpin1基因，该基因编码正常三酰甘油生物合成所需的Mg2+依赖性磷脂磷酸酶（PAP1）酶。受影响的动物出现明显的周围神经病变，其特征是髓磷脂降解，雪旺细胞去分化和增殖，神经传导速度降低。观察到的脱髓鞘是由PAP1酶底物磷脂酸（PA）的神经内膜积累介导的。此外，我们发现PA是雪旺细胞MEK-Erk通路的有效激活剂，并且这种激活对于PA诱导的脱髓鞘是必需的。因此，我们的研究结果揭示了PA在雪旺细胞命运决定中的惊人作用，并提供了影响脂质代谢的疾病与异常雪旺细胞功能之间直接联系的证据。
Lipids play crucial roles in many aspects of glial cell biology, affecting processes ranging from myelin membrane biosynthesis to axo-glial interactions. In order to study the role of lipid metabolism in myelinating glial cells, we specifically deleted in Schwann cells the Lpin1 gene, which encodes the Mg2+-dependent phosphatidate phosphatase (PAP1) enzyme necessary for normal triacylglycerol biosynthesis. The affected animals developed pronounced peripheral neuropathy characterized by myelin degradation, Schwann cell dedifferentiation and proliferation, and a reduction in nerve conduction velocity. The observed demyelination is mediated by endoneurial accumulation of the substrate of the PAP1 enzyme, phosphatidic acid (PA). In addition, we show that PA is a potent activator of the MEK-Erk pathway in Schwann cells, and that this activation is required for PA-induced demyelination. Our results therefore reveal a surprising role for PA in Schwann cell fate determination and provide evidence of a direct link between diseases affecting lipid metabolism and abnormal Schwann cell function.