Unveiling lipid dysregulation: lipidomics of mouse brain and myelin in Niemann–Pick disease type C1

Niemann–Pick Disease Type C1 (NPC1) is a fatal, neurodegenerative disorder, characterized by lysosomal lipid accumulation and dysmyelination. Previous studies have documented some lipid abnormalities in the null mouse (Npc1−/−) brain. However, the specific lipidomic alterations in severely affected brain regions, such as cerebellum and isolated myelin remain understudied. We present a comprehensive LC-MS-based lipidomic analysis of the cerebellum and cortex of Npc1−/− mice (Balb/c-Npc1) during disease progression stages, along with the first myelin lipidome characterization in NPC1 disease. Our results reveal that the cerebellum accumulates lipid species progressively, while the cortex shows an overall decline in lipid levels, indicating region-specific lipid dysregulation. Notably, bis(monoacylglycero)phosphates and their precursors exhibit significant accumulation, with a preference for docosahexaenoic acid (DHA)-containing species. Myelin-specific lipidomics demonstrated extensive dysregulation, particularly in cortical myelin, including striking accumulation of hydroxy-ceramides. These findings offer critical insight into the lipid perturbations under the loss of NPC1, and highlight lipid targets that may be crucial for therapeutic intervention and biomarker development. A comprehensive LC-MS-based lipidomic investigation of the brain and isolated myelin in a Niemann–Pick Disease Type C1 mouse model reveals regional and progressive lipid dysregulations.