Abstract
Niemann-Pick type C (NPC) is a neurological disorder with no cure. NPC proteins deliver cholesterol from endosomes to other compartments including trans-Golgi network (TGN) and endoplasmic reticulum (ER). Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) is a resident ER enzyme that converts cholesterol to cholesteryl esters for storage. Here, we report the surprising finding that in a mutant Npc1 mice, Acat1-deficiency delayed the onset of weight loss and declining motor skill, prolonged lifespan, delayed Purkinje neuron death, and improved hepatosplenic pathology. Furthermore, syntaxin 6, a cholesterol-binding t-SNARE normally localized to TGN, is mislocalized in mutant NPC cells. However, upon ACAT1 inhibition this mislocalization is corrected, and increase the level of a few proteins further downstream. Our results imply that ACAT1 inhibition diverts a cholesterol storage pool in a way that replenished the low cholesterol level in NPC-deficient TGN. Taking together, we identify ACAT1 inhibition as a potential therapeutic target for NPC treatment.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations
- ABCA1
- ATP-binding cassette protein A1
- ACAT/SOAT
- Acyl-coezyme A:cholesterol acyltransferase/sterol O-acyltransferase
- KO
- gene knockout;
- A1-/-, Acat1-/-
- ACAT1 gene ablation
- CD-M6PR
- cation-dependent mannose-6-phosphate receptors
- ER
- endoplasmic reticulum
- PM
- plasma membrane
- TGN
- trans-Golgi network;
- LE
- late endosomes
- LXRs
- liver X receptors
- NPC
- Niemann-Pick type C
- Npc1nmf/nmf, Npc1nmf, or Npc1nmf164
- An Npc1 disease mouse model with D1005G mutation
- NPA
- Niemann-Pick type A.