Cholesterol in Niemann-Pick Type C disease

Abstract

Niemann-Pick Type C (NPC) disease is associated with accumulation of cholesterol and other lipids in late endosomes/lysosomes in virtually every organ; however, neurodegeneration represents the fatal cause for the disease. Genetic analysis has identified loss-of-function mutations in NPC1 and NPC2 genes as the molecular triggers for the disease. Although the precise function of these proteins has not yet been clarified, recent research suggests that they orchestrate cholesterol efflux from late endosomes/lysosomes. NPC protein deficits result in impairment in intracellular cholesterol trafficking and dysregulation of cholesterol biosynthesis. Disruption of cholesterol homeostasis is also associated with deregulation of autophagic activity and early-onset neuroinflammation, which may contribute to the pathogenesis of NPC disease. This chapter reviews recent achievements in the investigation of disruption of cholesterol homeostasis-induced neurodegeneration in NPC disease, and provides new insight for developing a potential therapeutic strategy for this disorder.

Fig. 11.1

Ultrastructure of Purkinje cells in Npc1−/− and Npc1+/+ mice. A A Purkinje cell of a 6-week-old Npc1+/+ mice. Npc, nucleus of Purkinje cell. ER, endoplasmic reticulum; G, Golgi apparatus; L, lysosome; M, mitochondria. B A Purkinje cell of a 6-week-old Npc1−/− mice. Numerous vacuoles (arrowheads) of different sizes with various levels of electron-dense materials are present in the cytoplasm. C Lysosome-like structures exist in Purkinje cells in Npc1+/+ mice. D–F Morphology of various membranous vacuoles. Some of them are with double membranes (arrowheads), whereas others have multilamellated structures (arrows). Scale bars = 2 µm (A and B), 1 µm (C–F). (Adapted from Liao et al., 2007)