University of Wisconsin-Madison, School of Veterinary Medicine, Madison, Wisconsin 53706, USA.
J Neurosci. 2013 May 1;33(18):8088-100. doi: 10.1523/JNEUROSCI.0233-13.2013.
The Long-Evans shaker (les) rat has a mutation in myelin basic protein that results in severe CNS dysmyelination and subsequent demyelination during development. During this time, les oligodendrocytes accumulate cytoplasmic vesicles, including lysosomes and membrane-bound organelles. However, the mechanism and functional relevance behind these oligodendrocyte abnormalities in les have not been investigated. Using high-magnification electron microscopy, we identified the accumulations in les oligodendrocytes as early and late autophagosomes. Additionally, immunohistochemistry and Western blots showed an increase in autophagy markers in les. However, autophagy did not precede the death of les oligodendrocytes. Instead, upregulating autophagy promoted membrane extensions in les oligodendrocytes in vitro. Furthermore, upregulating autophagy in les rats via intermittent fasting increased the proportion of myelinated axons as well as myelin sheath thickness in les and control rats. Overall, this study provides insight into the abnormalities described in les as well as identifying a novel mechanism that promotes the survival and function of oligodendrocytes.
长爪沙鼠（les）有一种髓鞘碱性蛋白的突变，导致其中枢神经系统在发育过程中出现严重的脱髓鞘和随后的髓鞘脱失。在此期间，les 少突胶质细胞积累细胞质囊泡，包括溶酶体和膜结合细胞器。然而，les 中少突胶质细胞异常的机制和功能相关性尚未得到研究。使用高倍电子显微镜，我们发现 les 少突胶质细胞中的堆积物是早期和晚期自噬体。此外，免疫组织化学和 Western blot 显示 les 中自噬标志物增加。然而，自噬并没有先于 les 少突胶质细胞的死亡。相反，在体外上调自噬促进了 les 少突胶质细胞的膜延伸。此外，通过间歇性禁食在 les 大鼠中上调自噬增加了 les 和对照大鼠中有髓轴突的比例以及髓鞘厚度。总的来说，这项研究深入了解了 les 中描述的异常情况，并确定了一种促进少突胶质细胞存活和功能的新机制。
