Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, The Netherlands.
Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21383-8. doi: 10.1073/pnas.0905633106. Epub 2009 Nov 30.
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.
髓鞘形成需要大量增加神经胶质细胞膜的合成。在这里，我们证明了鞘磷脂合成的急性期受到固醇调节元件结合蛋白（SREBP）切割激活蛋白（SCAP）的调节，SCAP 是 SREBPs 的激活剂。雪旺细胞中 SCAP 的缺失导致胆固醇和脂肪酸合成的 SREBP 介导的基因表达丧失。雪旺细胞 SCAP 突变小鼠表现出先天性少突胶质细胞发育不全和异常步态。有趣的是，衰老的 SCAP 突变小鼠表现出部分功能恢复；它们表现出步态改善，并产生少量髓鞘，表明外部脂质的 SCAP 独立摄取缓慢。因此，细胞外脂蛋白部分挽救了 SCAP 突变雪旺细胞的髓鞘形成。然而，SCAP 突变的髓鞘从未达到正常厚度，并且具有与异常脂质组成一致的生物物理异常。这些数据表明，SCAP 介导的神经胶质细胞脂生成调节是髓鞘膜适当合成的关键，并且为影响脂质代谢的条件下雪旺细胞功能异常提供了深入了解。
