The intracellular cholesterol transporter NPC1 functions in late endosomes and lysosomes to efflux unesterified cholesterol, and its deficiency causes Niemann–Pick disease Type C, an autosomal recessive lysosomal disorder characterized by progressive neurodegeneration and early death. Here, we use single-nucleus RNA-seq on the forebrain of Npc1^−/− mice at P16 to identify cell types and pathways affected early in pathogenesis. Our analysis uncovers significant transcriptional changes in the oligodendrocyte lineage during developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. We identify upregulation of genes associated with neurogenesis and synapse formation in Npc1^−/− oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3. Npc1^−/− oligodendrocyte progenitor cells reproduce impaired maturation in vitro, and this phenotype is rescued by treatment with GSK-J4, a small molecule inhibitor of H3K27 demethylases. Moreover, mobilizing stored cholesterol in Npc1^−/− mice by a single administration of 2-hydroxypropyl-β-cyclodextrin at P7 rescues myelination, epigenetic marks, and oligodendrocyte gene expression. Our findings highlight an important role for NPC1 in oligodendrocyte lineage maturation and epigenetic regulation, and identify potential targets for therapeutic intervention.

细胞内胆固醇转运蛋白 NPC1 在晚期内涵体和溶酶体中发挥作用，流出未酯化的胆固醇，其缺陷会导致 C 型尼曼-皮克病，这是一种常染色体隐性遗传溶酶体疾病，其特征是进行性神经变性和早期死亡。在这里，我们在 P16的Npc1 ^−/−小鼠的前脑上使用单核 RNA 测序来识别在发病机制早期受影响的细胞类型和途径。我们的分析揭示了发育髓鞘形成过程中少突胶质细胞谱系的显着转录变化，并伴随着髓鞘形成少突胶质细胞成熟度的降低。我们发现Npc1中与神经发生和突触形成相关的基因上调^-/−少突胶质细胞系细胞，反映 H3K27me3 的基因沉默减弱。Npc1 ^{-/ -}少突胶质祖细胞在体外复制成熟受损的细胞，这种表型可以通过 GSK-J4（一种 H3K27 去甲基酶的小分子抑制剂）治疗来挽救。此外，通过在 P7 时单次施用 2-羟丙基-β-环糊精来动员Npc1 ^{−/−小鼠中储存的胆固醇，可以挽救髓鞘形成、表观遗传标记和少突胶质细胞基因表达。}我们的研究结果强调了 NPC1 在少突胶质细胞谱系成熟和表观遗传调控中的重要作用，并确定了治疗干预的潜在靶标。