Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in the NPC1 gene, causing lipid accumulation within late endosomes/lysosomes and resulting in progressive neurodegeneration. Although microglial activation precedes neuronal loss, it remains elusive whether loss of the membrane protein NPC1 in microglia actively contributes to NPC pathology. In a mouse model with depletion of NPC1 in myeloid cells, we report severe alterations in microglial lipidomic profiles, including the enrichment of bis(monoacylglycero)phosphate, increased cholesterol, and a decrease in cholesteryl esters. Lipid dyshomeostasis was associated with microglial hyperactivity, marked by an increase in translocator protein 18 kDa (TSPO). These hyperactive microglia initiated a pathological cascade resembling NPC-like phenotypes, including a shortened life span, motor impairments, astrogliosis, neuroaxonal pathology, and increased neurofilament light chain (NF-L), a neuronal injury biomarker. As observed in the mouse model, patients with NPC showed increased NF-L in the blood and microglial hyperactivity, as visualized by TSPO-PET imaging. Reduced TSPO expression in blood-derived macrophages of patients with NPC was measured after N -acetyl- l -leucine treatment, which has been recently shown to have beneficial effects in patients with NPC, suggesting that TSPO is a potential marker to monitor therapeutic interventions for NPC. Conclusively, these results demonstrate that myeloid dysfunction, driven by the loss of NPC1, contributes to NPC disease and should be further investigated for therapeutic targeting and disease monitoring.

中文翻译：

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小鼠骨髓细胞特异性 NPC1 丢失概括了 Niemann-Pick C 型病患者的小胶质细胞增生和神经变性


尼曼-匹克 C 型 （NPC） 病是一种遗传性溶酶体贮积症，主要由 NPC1 基因突变驱动，导致脂质在晚期内体/溶酶体内积累，导致进行性神经变性。尽管小胶质细胞激活先于神经元丢失，但小胶质细胞中膜蛋白 NPC1 的缺失是否积极导致 NPC 病理学仍然难以捉摸。在骨髓细胞中 NPC1 耗竭的小鼠模型中，我们报告了小胶质细胞脂质组学谱的严重改变，包括双（单酰基甘油）磷酸酯的富集、胆固醇增加和胆固醇酯的减少。脂质失态与小胶质细胞多动有关，其特征是易位蛋白 18 kDa （TSPO） 的增加。这些过度活跃的小胶质细胞引发了类似于 NPC 样表型的病理级联反应，包括寿命缩短、运动障碍、星形胶质细胞增生、神经轴突病理和神经元损伤生物标志物神经丝轻链 （NF-L） 增加。正如在小鼠模型中观察到的那样，NPC 患者表现出血液中 NF-L 的增加和小胶质细胞多动，如 TSPO-PET 成像所显示的那样。在 N-乙酰-l -亮氨酸治疗后测量 NPC 患者血液衍生巨噬细胞中 TSPO 表达降低，最近证明对 NPC 患者有益，表明 TSPO 是监测 NPC 治疗干预的潜在标志物。总之，这些结果表明，由 NPC1 缺失驱动的髓系功能障碍会导致 NPC 疾病，应进一步研究用于治疗靶向和疾病监测。