Lysosomal storage disorders (LSDs) are diseases characterized by the accumulation of macromolecules in the late endocytic system and are caused by inherited defects in genes that encode mainly lysosomal enzymes or transmembrane lysosomal proteins. Niemann-Pick type C disease (NPCD), a LSD characterized by liver damage and progressive neurodegeneration that leads to early death, is caused by mutations in the genes encoding the NPC1 or NPC2 proteins. Both proteins are involved in the transport of cholesterol from the late endosomal compartment to the rest of the cell. Loss of function of these proteins causes primary cholesterol accumulation, and secondary accumulation of other lipids, such as sphingolipids, in lysosomes. Despite years of studying the genetic and molecular bases of NPCD and related-lysosomal disorders, the pathogenic mechanisms involved in these diseases are not fully understood. In this review we will summarize the pathogenic mechanisms described for NPCD and we will discuss their relevance for other LSDs with neurological components such as Niemann- Pick type A and Gaucher diseases. We will particularly focus on the activation of signaling pathways that may be common to these three pathologies with emphasis on how the intra-lysosomal accumulation of lipids leads to pathology, specifically to neurological impairments. We will show that although the primary lipid storage defect is different in these three LSDs, there is a similar secondary accumulation of metabolites and activation of signaling pathways that can lead to common pathogenic mechanisms. This analysis might help to delineate common pathological mechanisms and therapeutic targets for lysosomal storage diseases.

溶酶体贮积症（LSD）是特征在于大分子在晚期内吞系统中积累的疾病，并且是由主要编码溶酶体酶或跨膜溶酶体蛋白的基因的遗传缺陷引起的。Niemann-Pick C型疾病（NPCD）是一种LSD，其特征是肝损伤和进行性神经变性导致早期死亡，是由编码NPC1或NPC2蛋白的基因突变引起的。两种蛋白质都参与胆固醇从内体晚期区室到细胞其余部分的胆固醇运输。这些蛋白质功能的丧失导致溶酶体中的主要胆固醇积累和其他脂质（如鞘脂）的次级积累。尽管对NPCD和相关溶酶体疾病的遗传和分子基础进行了多年研究，这些疾病涉及的致病机制尚不完全清楚。在这篇综述中，我们将总结针对NPCD的致病机制，并讨论它们与其他具有神经系统成分的LSD（如Niemann-Pick A型和Gaucher病）的相关性。我们将特别关注这三种病理可能共有的信号传导途径的激活，重点是溶酶体内脂质的蓄积如何导致病理，特别是神经功能障碍。我们将显示，尽管在这三个LSD中主要的脂质存储缺陷有所不同，但是代谢物的类似次级积累和信号传导途径的激活可能导致常见的致病机制。