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.

中文翻译：

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Acat1基因KO可恢复突变NPC1细胞中TGN胆固醇缺乏症并延长突变Npc1小鼠的寿命

Niemann-Pick C型（NPC）是一种无法治愈的神经系统疾病。NPC蛋白将胆固醇从内体传递到其他区室，包括反高尔基网络（TGN）和内质网（ER）。酰基辅酶A：胆固醇酰基转移酶1（ACAT1）是一种常驻ER酶，可将胆固醇转化为胆固醇酯以进行存储。在这里，我们报告了令人惊讶的发现，即在突变的Npc1小鼠中，Acat1缺乏症延迟了体重减轻和运动技能下降的发作，延长了寿命，延缓了浦肯野神经元死亡，并改善了肝脾病理。此外，语法素6，通常定位于TGN的胆固醇结合性t-SNARE，在突变的NPC细胞中定位不正确。但是，在抑制ACAT1后，这种错误定位得以纠正，并在下游进一步增加了一些蛋白质的水平。我们的结果表明，ACAT1抑制以补充NPC缺陷型TGN中低胆固醇水平的方式转移了胆固醇存储库。综上所述，我们确定ACAT1抑制是NPC治疗的潜在治疗靶标。