title: Partial blockage of sterol biosynthesis with a squalene synthase inhibitor in early postnatal Niemann-Pick type C npcnih null mice brains reduces neuronal cholesterol accumulation, abrogates astrogliosis, but may inhibit myelin maturation.
abstract: Niemann-Pick C disease (NPC) is a fatal, neurovisceral genetic disorder. Cell culture studies showed that NPC1 or NPC2 mutations cause malfunctions in cellular cholesterol trafficking and lead to accumulation of cholesterol and other lipids in the late endo/lysosomes. Previous work showed that neuronal cholesterol accumulation occurs in the brains of young postnatal NPC1-/- mice. Here, to evaluate the potential of partial blockage of cholesterol biosynthesis as a therapy for the NPC disease, we first developed a simple method to monitor the relative rates of lipid biosynthesis in mice brains. We next administered squalene synthase inhibitor (SSI) CP-340868 to young mice. The results show that treating 8-day-old NPC1-/- mice with CP-340868 for 6 days significantly inhibits cholesterol biosynthesis in the mice brains. It reduces neuronal cholesterol accumulation, reduces GM3 ganglioside accumulation, and diminishes astrogliosis in the brain. These results suggest that neuronal cholesterol accumulation contributes to early pathogenesis in the NPC1-/- mice brains. The SSI treatment also reduced brain galactolipid content, suggesting that blocking endogenous cholesterol synthesis in the young mice brains may disrupt the normal myelin maturation processes. The methods described in the current work have general applicability for lipid metabolism studies in mice brains in various pathophysiological conditions.
authors.affiliation: Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Reid
authors.forename: Song
authors.initials: S
authors.lastname: Lin
authors.forename: Marie T
authors.initials: MT
authors.lastname: Vanier
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Ohno-Iwashita
authors.forename: H James
authors.initials: HJ
authors.lastname: Harwood
authors.forename: William F
authors.initials: WF
authors.lastname: Hickey
authors.forename: Catherine C Y
authors.initials: CC
authors.lastname: Chang
authors.forename: Ta Yuan
authors.initials: TY
authors.lastname: Chang
mesh_terms: D000085:Acetates / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005732:Gangliosides / Q000378:metabolism; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D000077296:Niemann-Pick C1 Protein; D011506:Proteins / Q000235:genetics*; D013261:Sterols / Q000378:metabolism*; D013997:Time Factors; D014316:Tritium / Q000378:metabolism
chemical_list: D000085:Acetates; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D005732:Gangliosides; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D013261:Sterols; D014316:Tritium; D002784:Cholesterol; D008148:Lovastatin; D013186:Farnesyl-Diphosphate Farnesyltransferase