Organelles: Lysosomal storage disease NPC

Niemann–Pick type C (NPC) disease is a rare, autosomal recessive lysosomal storage disorder that is predominantly caused by mutations in the NPC1 gene, which codes for the 133-kilodalton (kDa) protein NPC1 and in rarer cases caused by mutations in the NPC2 gene, which codes for the 14.9-kDa protein NPC2. Defects in lipid transport in lysosomes and late endosomes are most likely critical to disease pathogenesis. Cholesterol has been widely recognized as the major storage lipid involved, and sphingomyelin and glycosphingolipid involvement have also been characterized in both animal models and patients with NPC. The isolation of the NPC1 and NPC2 genes has allowed for elucidation of the role played by NPC proteins in cholesterol transport.

Neurons are known to obtain cholesterol through endogenous synthesis or uptake of lipoprotein cholesterol particles produced and released within the central nervous system (CNS). Following the internalization of these particles by target cells, unesterified cholesterol is transported from the endosomal/lysosomal system to the Golgi complex and endoplasmic reticulum, where it is processed and used as a substrate for further reactions. Brown and Goldstein suggested that the NPC1 and NPC2 proteins perform coordinated actions during this process – NPC2 binds unesterified cholesterol and transfers it to the N-terminal domain of membrane-associated NPC1, thereby allowing its transport out of the late endosome/lysosome compartment. However, in the absence of NPC1 and NPC2, lipoprotein cholesterol particles remain trapped in late endosome/lysosome system, greatly reducing cholesterol levels in the Golgi complex and endoplasmic reticulum and causing deleterious effects on all processes that depend on proper membrane composition.

Effects of cholesterol transport in Niemann–Pick disease type C are illustrated in Figure 1.

Figure 1 Altered cholesterol trafficking in normal conditions (A) and in the absence of NPC1 or NPC2 (B)