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.

The life cycle of the low-density lipoprotein receptor

“…Endolysosomal trafficking of the LDLR ligand is likely to depend on the two-pore channel TPC2, whereas TPC1 is involved in Ca 2þ signaling, which seems to be needed for the endolysosomal fusion processes [8]. The transfer of cholesterol into the cytosol is mediated by the Niemann-Pick disease proteins, type C1 and C2 (NPC1 and NPC2) [9].…”

Lysosomal Lipid Storage Diseases

“…Lysosomal lipid storage diseases comprise mainly the sphingolipidoses, Niemann-Pick type C disease (NPC), and Wolman disease, including the less severe form of this disease, called cholesteryl ester storage. NPC is a complex lipid storage disease mainly characterized by the accumulation of unesterified cholesterol in the late endosomal/lysosomal compartment (Bi and Liao 2010). The sphingolipidoses are caused by defects in genes encoding proteins involved in the lysosomal degradation of sphingolipids (Kolter and Sandhoff 2006).…”

Association of Niemann-Pick disease, type C2 (NPC2) polymorphisms with obesity in Korean population

“…Genetic study has revealed that loss-of-function mutations in NPC1 and NPC2 genes as the molecular triggers for the disease 22 . NPC protein deficits lead to impairment in intracellular cholesterol trafficking and dysregulation of cholesterol biosynthesis 23 . Blom et al 24 reported that NPC2 was upregulated and accumulated in cholesterol storing endocytic organelles.…”