SCAP is required for timely and proper myelin membrane synthesis
SCAP is required for timely and proper myelin membrane synthesis
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DOI：
10.1073/pnas.0905633106
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发表时间：
2009-12-15
影响因子：
11.1
通讯作者：
Smit, August. B.
中科院分区：
文献类型：
--
作者：
Verheijen, Mark H. G.;Camargo, Nutabi;Smit, August. B.
髓鞘形成需要神经胶质细胞膜合成的大量增加。在这里，我们证明了髓磷脂脂质合成的急性期是由固醇调节元件结合蛋白（SREBP）裂解激活蛋白（SCAP），SREBP的激活剂。雪旺细胞中SCAP的缺失导致SREBP介导的涉及胆固醇和脂肪酸合成的基因表达的丧失。雪旺细胞SCAP突变小鼠表现出先天性髓鞘形成不足和步态异常。有趣的是，衰老的SCAP突变小鼠表现出部分功能恢复;它们表现出改善的步态，并产生少量的髓鞘，表明缓慢的SCAP-独立的外部脂质摄取。因此，细胞外脂蛋白部分挽救髓鞘SCAP突变体雪旺细胞。然而，SCAP突变髓鞘从未达到正常厚度，并有生物物理异常与异常脂质组成一致。这些数据表明，SCAP介导的神经胶质细胞脂肪生成的调节是髓鞘膜的正确合成的关键，并提供了在影响脂质代谢的条件下异常雪旺细胞功能的见解。
Myelination requires a massive increase in glial cell membrane synthesis. Here, we demonstrate that the acute phase of myelin lipid synthesis is regulated by sterol regulatory element-binding protein (SREBP) cleavage activation protein (SCAP), an activator of SREBPs. Deletion of SCAP in Schwann cells led to a loss of SREBP-mediated gene expression involving cholesterol and fatty acid synthesis. Schwann cell SCAP mutant mice show congenital hypomyelination and abnormal gait. Interestingly, aging SCAP mutant mice showed partial regain of function; they exhibited improved gait and produced small amounts of myelin indicating a slow SCAP-independent uptake of external lipids. Accordingly, extracellular lipoproteins partially rescued myelination by SCAP mutant Schwann cells. However, SCAP mutant myelin never reached normal thickness and had biophysical abnormalities concordant with abnormal lipid composition. These data demonstrate that SCAP-mediated regulation of glial lipogenesis is key to the proper synthesis of myelin membrane, and provide insight into abnormal Schwann cell function under conditions affecting lipid metabolism.