Genetic variations and treatments that affect the lifespan of the NPC1 mouse

Abstract

Niemann-Pick type C (NPC) disease is a multisystem disorder caused primarily by a mutation in the npc1 gene. These studies evaluated the effect of genetic background, deletion of additional genes, and administration of several agents on the age at death in a murine model of this disorder. Such factors as differing strain background or genetic drift within a given background in the npc1 2/2 mouse significantly altered the age at death and the degree of organ disease. Genetic deletion of Siat9 (GM3 synthetase) or Nr1h2 [liver X receptor (LXR)b] shortened the life of the npc1 2/2 animals. Daily treatment of the npc1 2/2 mice with an LXR agonist or administration of a single dose of cyclodextrin, with or without the neurosteroid allopregnanolone, significantly slowed neurodegeneration and increased the lifespan of these animals. These data illustrate that the age at death of the npc1 2/2 mouse can be significantly influenced by many factors, including differences in strain background, other inactivating gene mutations (Siat9 and lxrb), and administration of agents such as LXR agonists and, particularly, cyclodextrin. It is currently not clear which of these effects is nonspecific or which might relate directly to the molecular defect present in the NPC1 syndrome.-

Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells

“…This is consistent with its better ability to extract cholesterol from biologic membranes (13)(14)(15). This observation may be important because relatively high amounts of HPβCD need to be injected to obtain a partial therapeutic effect (8)(9)(10)(11)(12). Additionally, the observation that CD works from inside LE/LY suggests that modifications that target CDs for endocytic uptake and retention might significantly enhance its potency.…”

“…All of the studies showing CD efficacy in murine models of NPC1 used HPβCD for treatment (8)(9)(10)(11). However, cell culture studies have shown that MβCD is more potent in extracting, delivering, and exchanging cholesterol than HPβCD (13)(14)(15).…”

“…Clinical manifestations of NPC disease include neuronal degeneration, hepatosplenomegaly, and effects in other organs (1). No effective treatment is currently available for NPC disease (7), but recent studies involving administration of hydroxypropyl-β-cyclodextrin (HPβCD) in npc1 −/− mice showed improvements in viability, hepatopathology, and neuropathology, including clearance of cholesterol and glycosphingolipids (8)(9)(10)(11)(12). These animal studies were not designed to address the molecular and cellular mechanisms by which cyclodextrins (CDs) could reduce the cholesterol accumulation in LSOs.…”

NPC1/NPC2 function as a tag team duo to mobilize cholesterol

“…Here, both pharmacological chaperones (PCs) (i.e., small molecules such as cholesterol analogs that could bind and stabilize the fold) or a new class of compounds we refer to as proteostasis regulators (PRs) (19) that alter the cellular folding environment to ''repair'' the variant fold may favor repopulation of the LE with functional NPC1 and restoration of acceptor function. Strikingly, as proofof-principle of the key insights provided by Infante et al (13), cyclodextrins have recently been reported to correct NPC1 null mouse models of disease (20,21). Here, cholesterol binding activity of either internalized cyclodextrin or, possibly, the presence of an extracellular sink for cholesterol could supplement the shuttle activity of endogenous NPC2 to transfer cholesterol from internal membranes to favor efflux via ABCA1 or vesicular recycling pathways.…”

“…Indeed, combination therapy of cholesterol mobilization with cyclodextrin-like cholesterol binding scaffolds (20,21) and a PC/PR (18) may prove to be synergistic to create a substantially improved trafficking and function environment as Kelly and colleagues (23) have demonstrated recently for Gaucher's disease.…”