Walkley Steven U, Suzuki Kinuko
Sidney Weisner Laboratory of Genetic Neurological Disease Department of Neuroscience, Rose F Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Biochim Biophys Acta. 2004 Oct 11;1685(1-3):48-62. doi: 10.1016/j.bbalip.2004.08.011.
Genetic deficiency of NPC1 or NPC2 results in a devastating cholesterol-glycosphingolipidosis of brain and other organs known as Niemann-Pick type C (NPC) disease. While NPC1 is a transmembrane protein believed involved in retroendocytic shuttling of substrate(s) to the Golgi and possibly elsewhere in cells as part of an essential recycling/homeostatic control mechanism, NPC2 is a soluble lysosomal protein known to bind cholesterol. The precise role(s) of NPC1 and NPC2 in endosomal-lysosomal function remain unclear, nor is it known whether the two proteins directly interact as part of this function. The pathologic features of NPC disease, however, are well documented. Brain cells undergo massive intracellular accumulation of glycosphingolipids (lactosylceramide, glucosylceramide, GM2 and GM3 gangliosides) and cholesterol and concomitant distortion of neuron shape (meganeurite formation). In neurons from humans with NPC disease the metabolic defects and storage often lead to extensive growth of new, ectopic dendrites (possibly linked to ganglioside sequestration) as well as formation of neurofibrillary tangles (NFTs) (possibly linked to dysregulation of cholesterol metabolism). Other features of cellular pathology in NPC disease include fragmentation of the Golgi apparatus and neuroaxonal dystrophy, though reasons for these changes remain largely unknown. As the disease progresses, neurodegeneration is also apparent for neurons in some brain regions, particularly Purkinje cells of the cerebellum, but the basis of this selective neuronal vulnerability is unknown. The NPC1 protein is evolutionarily conserved with homologues reported in yeast to humans; NPC2 is reported in C. elegans to humans. While neurons in mammalian models of NPC1 and NPC2 diseases exhibit many changes that are remarkably similar to those in humans (e.g., endosomal/lysosomal storage, Golgi fragmentation, neuroaxonal dystrophy, neurodegeneration), a reduced degree of ectopic dendritogenesis and an absence of NFTs in these species suggest important differences in the way lower mammalian neurons respond to NPC1/NPC2 loss of function.
NPC1或NPC2的基因缺陷会导致一种严重的脑和其他器官的胆固醇-糖鞘脂贮积病，即尼曼-匹克C型（NPC）病。NPC1是一种跨膜蛋白，被认为参与底物的逆向内吞转运至高尔基体以及细胞内其他部位，作为一种重要的循环/稳态控制机制的一部分；而NPC2是一种可溶性溶酶体蛋白，已知其可结合胆固醇。NPC1和NPC2在内体-溶酶体功能中的精确作用仍不清楚，也不知道这两种蛋白是否作为该功能的一部分直接相互作用。然而，NPC病的病理特征已有充分记录。脑细胞会发生糖鞘脂（乳糖基神经酰胺、葡萄糖基神经酰胺、GM2和GM3神经节苷脂）和胆固醇的大量细胞内蓄积，同时神经元形态会发生扭曲（形成巨神经突）。在患有NPC病的人类神经元中，代谢缺陷和蓄积常常导致新的异位树突广泛生长（可能与神经节苷脂隔离有关）以及神经原纤维缠结（NFTs）的形成（可能与胆固醇代谢失调有关）。NPC病细胞病理学的其他特征包括高尔基体碎片化和神经轴突营养不良，不过这些变化的原因在很大程度上仍不清楚。随着疾病进展，某些脑区的神经元，特别是小脑的浦肯野细胞，神经退行性变也很明显，但这种选择性神经元易损性的基础尚不清楚。NPC1蛋白在进化上是保守的，从酵母到人类都有同源物报道；NPC2从秀丽隐杆线虫到人类都有报道。虽然NPC1和NPC2疾病的哺乳动物模型中的神经元表现出许多与人类非常相似的变化（例如，内体/溶酶体贮积、高尔基体碎片化、神经轴突营养不良、神经退行性变），但这些物种中异位树突形成程度降低以及缺乏NFTs表明，低等哺乳动物神经元对NPC1/NPC2功能丧失的反应方式存在重要差异。
