Spatial lipidomics reveals demyelination and remyelination dynamics in the mouse brain.

IF 4.1 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mikolaj Opielka, Krzysztof Urbanowicz, Klaudia Konieczna-Wolska, Elisabeth Müller, Oliwier Krajewski, Maureen Feucherolles, Qiuqin Zhou, Michal Bienkowski, Gilles Frache, Carsten Hopf, Lucas Schirmer, Aleksandra Rutkowska, Ryszard T Smolenski
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引用次数: 0

Abstract

Myelin pathology in demyelinating diseases is accompanied by lipid remodeling that remains challenging to characterize at spatial level using traditional mass spectrometry. We developed an optimized AP-MALDI-Orbitrap MSI pipeline, incorporating sample preparation improvements and mass recalibration, to investigate lipid dynamics in the cuprizone (CPZ) mouse model of demyelination. Dual-modality, untargeted lipid profiling was performed to map spatially resolved lipid alterations during demyelination and spontaneous remyelination in two key brain areas of male mice: corpus callosum (CC) and cortex (Ctx), with lipid identifications benchmarked against 4D-LC-TIMS-MS/MS. Demyelinated regions were identified using Black Gold II staining. Using 1 ppm mass tolerance, we annotated 154 and 133 lipids at the sum-composition level in CC and Ctx, respectively, with 60% validated by LC-MS/MS. Spatial lipid profiling revealed CPZ-induced alterations in sphingolipids, sulfatides, and glycerophospholipids, supported by reanalysis of a published snRNA-seq dataset from a mouse CPZ model. Long-chain ceramides (Cer) and hexosylceramides (HexCer) were reduced in demyelinated regions, with partial, region-specific recovery during remyelination. Short-chain sulfatides (SHexCer), sphingomyelins (SM) and seminolipids transiently increased in the CC during demyelination, while long-chain sulfatides decreased in both CC and Ctx. Additionally, we observed demyelination-induced upregulation of polyunsaturated glycerophospholipids in CC and phosphatidylinositols (PI) in cortex. Lipid subclass changes emerged as reliable markers of both demyelination and remyelination in the mouse brain. Region-specific alterations in lipid metabolism provide new insights into the processes of de- and remyelination. Notably, remyelinated fibers have a distinct lipid profile compared to intact myelin, suggesting that lipid-based therapeutic strategies could improve myelin repair.

空间脂质组学揭示小鼠脑内脱髓鞘和再脱髓鞘动力学。
脱髓鞘疾病中的髓磷脂病理伴随着脂质重塑,使用传统的质谱法在空间水平上进行表征仍然具有挑战性。我们开发了一种优化的AP-MALDI-Orbitrap MSI管道,结合样品制备改进和质量重新校准,研究铜酮(CPZ)小鼠脱髓鞘模型中的脂质动力学。采用双模态、非靶向脂质分析方法,绘制雄性小鼠两个关键脑区(胼胝体(CC)和皮层(Ctx))脱髓鞘和自发髓鞘再生过程中脂质在空间上的变化,脂质鉴定以4D-LC-TIMS-MS/MS为基准。黑金II染色法鉴定脱髓鞘区。使用1 ppm的质量公差,我们分别在CC和Ctx的和组成水平上注释了154和133种脂质,其中60%通过LC-MS/MS验证。空间脂质分析显示CPZ诱导鞘脂、硫脂和甘油磷脂的改变,这得到了来自小鼠CPZ模型的已发表snRNA-seq数据集的重新分析的支持。长链神经酰胺(Cer)和己糖神经酰胺(HexCer)在脱髓鞘区域减少,在脱髓鞘再生过程中有部分区域特异性恢复。短链硫脂(shexer)、鞘磷脂(SM)和半脂在脱髓鞘过程中短暂增加,而长链硫脂在CC和Ctx中均下降。此外,我们观察到脱髓鞘诱导的CC多不饱和甘油磷脂和皮质磷脂酰肌醇(PI)的上调。脂质亚类的变化是小鼠大脑中脱髓鞘和再髓鞘形成的可靠标志。脂质代谢的区域特异性改变为脱髓鞘和再生过程提供了新的见解。值得注意的是,与完整的髓鞘相比,再髓鞘纤维具有明显的脂质特征,这表明基于脂质的治疗策略可以改善髓鞘修复。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Lipid Research
Journal of Lipid Research 生物-生化与分子生物学
CiteScore
11.10
自引率
4.60%
发文量
146
审稿时长
41 days
期刊介绍: The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.
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