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Abstract：
Niemann-Pick type C (NPC) disease is a rare progressive lysosomal lipid storage disorder that manifests with a heterogeneous spectrum of clinical syndromes, including visceral, neurological and psychiatric symptoms. This monogenetic autosomal recessive disease is largely caused by mutations in the NPC1 gene, which controls intracellular lipid homeostasis. Vesicle-mediated endo-lysosomal lipid trafficking and non-vesicular lipid exchange via inter-organelle membrane contact sites are both regulated by the NPC1 protein. Loss of NPC1 function therefore triggers intracellular accumulation of diverse lipid species, including cholesterol, glycosphingolipids, sphingomyelin and sphingosine. The NPC1-mediated dysfunction of lipid transport has severe consequences for all brain cells, leading to neurodegeneration. Besides the cell-autonomous contribution of neuronal NPC1, aberrant NPC1 signalling in other brain cells is critical for the pathology. We discuss here the importance of endo-lysosomal dysfunction and a tight crosstalk between neurons, oligodendrocytes, astrocytes and microglia in NPC pathology. We strongly believe that a cell-specific rescue may not be sufficient to counteract the severity of the NPC pathology, but targeting common mechanisms, such as endo-lysosomal and lipid trafficking dysfunction, may ameliorate NPC pathology. This article is part of a discussion meeting issue \'Understanding the endo-lysosomal network in neurodegeneration\'.
摘要：
Niemann-PickC型（NPC）疾病是一种罕见的进行性溶酶体脂质贮积症，表现为临床综合征的异质性，包括内脏，神经和精神症状。这种单基因常染色体隐性遗传病主要是由NPC1基因突变引起的，控制细胞内脂稳态。囊泡介导的内溶酶体脂质运输和通过细胞器膜接触位点的非囊泡脂质交换均受NPC1蛋白调节。因此，NPC1功能的丧失会触发不同脂质物种的细胞内积累，包括胆固醇,鞘糖脂，鞘磷脂和鞘氨醇。NPC1介导的脂质转运功能障碍对所有脑细胞都有严重的后果，导致神经变性.除了神经元NPC1的细胞自主贡献外，其他脑细胞中异常的NPC1信号传导对于病理至关重要。我们在这里讨论了内溶酶体功能障碍和神经元之间紧密串扰的重要性，少突胶质细胞,NPC病理学中的星形胶质细胞和小胶质细胞。我们坚信，细胞特异性抢救可能不足以抵消NPC病理学的严重程度，但是针对共同的机制，如内溶酶体和脂质运输功能障碍，可以改善NPC病理学。本文是讨论会议议题“了解神经变性的内溶酶体网络”的一部分。
