Wu Lei, Wang Fang, Moncman Carole L, Pandey Mritunjay, Clarke Harrison A, Frazier Hilaree N, Young Lyndsay E A, Gentry Matthew S, Cai Weikang, Thibault Olivier, Sun Ramon C, Andres Douglas A
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, KY 40536, USA.
Department of Neuroscience, College of Medicine, University of Kentucky, KY 40536, USA.
Heliyon. 2023 Sep 23;9(10):e20384. doi: 10.1016/j.heliyon.2023.e20384. eCollection 2023 Oct.
Oligodendrocytes (OLs) generate lipid-rich myelin membranes that wrap axons to enable efficient transmission of electrical impulses. Using a knockout mouse model and high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) coupled with MS-based lipidomic analysis to determine the contribution of RIT1 to lipid homeostasis. Here, we report that RIT1 loss is associated with altered lipid levels in the central nervous system (CNS), including myelin-associated lipids within the corpus callosum (CC). Perturbed lipid metabolism was correlated with reduced numbers of OLs, but increased numbers of GFAP glia, in the CC, but not in grey matter. This was accompanied by reduced myelin protein expression and axonal conduction deficits. Behavioral analyses revealed significant changes in voluntary locomotor activity and anxiety-like behavior in mice. Together, these data reveal an unexpected role for RIT1 in the regulation of cerebral lipid metabolism, which coincide with altered white matter tract oligodendrocyte levels, reduced axonal conduction velocity, and behavioral abnormalities in the CNS.
少突胶质细胞（OLs）产生富含脂质的髓鞘膜，包裹轴突以实现电冲动的高效传导。利用基因敲除小鼠模型以及高分辨率基质辅助激光解吸/电离质谱成像（MALDI-MSI）结合基于质谱的脂质组学分析来确定RIT1对脂质稳态的作用。在此，我们报告RIT1缺失与中枢神经系统（CNS）脂质水平改变有关，包括胼胝体（CC）内与髓鞘相关的脂质。脂质代谢紊乱与CC中OL数量减少相关，但与灰质中OL数量减少无关，而CC中GFAP胶质细胞数量增加。这伴随着髓鞘蛋白表达减少和轴突传导缺陷。行为分析显示小鼠的自发运动活动和焦虑样行为有显著变化。总之，这些数据揭示了RIT1在调节脑脂质代谢中的意外作用，这与白质束少突胶质细胞水平改变、轴突传导速度降低以及CNS中的行为异常相一致。
