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(-/-) 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)beta] shortened the life of the npc1(-/-) animals. Daily treatment of the npc1(-/-) 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(-/-) mouse can be significantly influenced by many factors, including differences in strain background, other inactivating gene mutations (Siat9 and lxrbeta), 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.
Highlights
Niemann-Pick type C (NPC) disease is a multisystem disorder caused primarily by a mutation in the npc1 gene
Whereas both colonies were maintained on a BALB/c background, npc12/2 animals from the University of Texas Southwestern (UTSW) colony lived significantly longer (89 6 1.4 days) than those from the Jackson colony (80 6 0.8 days) when observed during the same time period (Fig. 1A)
Introducing the C57BL/6 and 129/SvJ backgrounds from the ldlr2/2 animals into the BALB/c npc12/2 mice decreased the age at death to 79 6 1.0 days, whereas the similar, mixed strain background derived from the abca12/2 mice prolonged lifespan to 91 6 1.1 days (Fig. 1B)
Summary
Niemann-Pick type C (NPC) disease is a multisystem disorder caused primarily by a mutation in the npc gene. Treatment of the npc12/2 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 npc12/2 mouse can be significantly influenced by many factors, including differences in strain background, other inactivating gene mutations (Siat and lxrb), and administration of agents such as LXR agonists and, cyclodextrin. In mice homozygous for this mutation, and with a BALB/c genetic background, the concentration of cholesterol becomes increased with age in nearly every organ, and there is neonatal cholestasis, liver cell death, pulmonary dysfunction, and selective nerve cell death [4,5,6,7,8] Despite this block in intracellular sterol movement, an increased rate of cholesterol synthesis within the cytoplasmic compartment allows for essentially normal rates of plasma membrane sterol turnover, bile acid synthesis, and steroid hormone production [9, 10].
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