Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches

Abstract

Cholesterol is an important lipid of mammalian cells. Its unique physicochemical properties modulate membrane behavior and it serves as the precursor for steroid hormones, oxysterols and vitamin D. Cholesterol is effluxed from the late endosomes/lysosomes via the concerted action of at least two distinct proteins: Niemann-Pick C (NPC)1 and NPC2. Mutations in these two proteins manifest as NPC disease - a very rare, usually fatal, autosomal, recessive, neurovisceral, lysosomal storage disorder. In this review, we discuss the possible mechanisms of action for NPC1 and NPC2 in mediating cholesterol efflux, as well as the different therapeutic approaches being pursued for the treatment of this lipid storage disorder.

Figure 1

Model for NPC1, NPC2 and cyclodextrin action in cholesterol efflux from LE/LY. In normal cells, cholesteryl esters are hydrolyzed by LAL to produce free cholesterol and fatty acid (1), then free cholesterol is transferred to NPC2 (2), and subsequently to NPC1(NTD) (3). Free cholesterol is then delivered to the luminal leaflet of the limiting membrane of LE/LY (4), where it can spontaneously flip to the cytosolic side (5) and then be carried to its various destinations in the cell by cytoplasmic carriers (6). In the absence of functional NPC2 or NPC1, cyclodextrins can replace their functions in promoting cholesterol efflux (7, 8), bypassing steps 2–4. BMP stimulates the activities of LAL and NPC2. In the CNS, free cholesterol is shuttled from the glia to neurons via an ApoE complex, and no plasma LDL is believed to permeate the blood-brain barrier. Thus, all the CNS cholesterol is supplied through endogenous synthesis.