Acat1/Soat1 knockout extends the mutant Npc1 mouse lifespan and ameliorates functional deficiencies in multiple organelles of mutant cells

Abstract

Significance Niemann-Pick type C disease (NPCD) is an incurable genetic neurological disorder. Cells with NPC mutations fail to export cholesterol from endosomal organelle to multiple other organelles. ACAT1 is an enzyme that converts cholesterol to cholesteryl esters for storage. In mutant NPC cells, cholesterol storage still occurs, although at reduced rate. Here we show that in mutant NPC cells, ACAT1 blockade (A1B) decreases cholesterol storage such that it can be utilized to fulfill cholesterol needs in multiple organelles. In mutant NPC1 mice, Acat1 gene knockout reduces pathological onset and prolongs the lifespan by 34%. This work identifies ACAT1 as a target to treat NPCD and may help to explain why A1B has been reported to ameliorate preclinical models for Alzheimer’s disease.