Ma Tiantian, Mao Wei, Zhang Shaohua, Wang Yaqing, Wang Tao, Liu Jinghua, Shi Lei, Yu Xiang, Xue Rong, Shui Guanghou, Xu Zhiheng
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Life Metab. 2023 Mar 23;2(2):load010. doi: 10.1093/lifemeta/load010. eCollection 2023 Apr.
Lipid-rich myelin is a special structure formed by oligodendrocytes wrapping neuronal axons. Abnormal myelin sheath is associated with many neurological diseases. Meningioma-expressed antigen 6 (Mea6)/cutaneous T cell lymphoma-associated antigen 5C (cTAGE5C) plays an important role in vesicle trafficking from the endoplasmic reticulum (ER) to Golgi, and conditional knockout (cKO) of in the brain significantly affects neural development and brain function. However, whether the impaired brain function involves the development of oligodendrocytes and white matter beyond neurons remains unclear. In this study, by using different models of diffusion magnetic resonance imaging, we showed that cKO of in oligodendrocytes leads to significant impairment of the gross and microstructure of the white matter, as well as a significant decrease of cholesterol and triglycerides in brains. Our lipidomic analysis of purified myelin sheath for the first time showed that elimination in oligodendrocytes significantly altered the lipid composition in myelin lipidome, especially the proportion of very long chain fatty acids (VLCFAs). In particular, the levels of most VLCFA-containing phosphatidylcholines were substantially lower in the myelin sheath of the cKO mice. The reduction of VLCFAs is likely due to the downregulated expression of (). Our study of an animal model with white matter malformation and the comprehensive lipid profiling would provide clues for future studies of the formation of myelin sheath, myelin lipids, and the pathogenesis of white matter diseases.
富含脂质的髓鞘是少突胶质细胞包裹神经元轴突形成的特殊结构。髓鞘异常与许多神经系统疾病相关。脑膜瘤表达抗原6（Mea6）/皮肤T细胞淋巴瘤相关抗原5C（cTAGE5C）在内质网（ER）到高尔基体的囊泡运输中起重要作用，在脑中条件性敲除（cKO）会显著影响神经发育和脑功能。然而，脑功能受损是否涉及除神经元外少突胶质细胞和白质的发育仍不清楚。在本研究中，通过使用不同的扩散磁共振成像模型，我们表明少突胶质细胞中cKO会导致白质的大体和微观结构显著受损，以及脑中胆固醇和甘油三酯显著减少。我们首次对纯化的髓鞘进行脂质组学分析表明，少突胶质细胞中cKO显著改变了髓鞘脂质组中的脂质组成，尤其是超长链脂肪酸（VLCFA）的比例。特别是，cKO小鼠髓鞘中大多数含VLCFA的磷脂酰胆碱水平大幅降低。VLCFA的减少可能是由于（）表达下调。我们对白质畸形动物模型的研究和全面的脂质谱分析将为未来髓鞘形成、髓鞘脂质以及白质疾病发病机制的研究提供线索。
