Mukherjee Sushmita, Maxfield Frederick R
Department of Biochemistry, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Biochim Biophys Acta. 2004 Oct 11;1685(1-3):28-37. doi: 10.1016/j.bbalip.2004.08.009.
Niemann-Pick type C, or NPC for short, is an early childhood disease exhibiting progressive neurological degeneration, associated with hepatosplenomegaly in some cases. The disease, at the cellular level, is a result of improper trafficking of lipids such as cholesterol and glycosphingolipids (GSLs) to lysosome-like storage organelles (LSOs), which become engorged with these lipids. It is believed that the initial defect in trafficking, whether of cholesterol or a GSL, results in an eventual traffic jam in these LSOs. This leads to the retention of not only other lipids, but also of transmembrane proteins that transiently associate with the late endosomes (LE) in normal cells, on their way to other cellular destinations such as the trans-Golgi network (TGN). In this review, we discuss the biophysical properties of lipids and cholesterol that might determine their intracellular itineraries, and how these itineraries are altered in NPC cells, which have defects in the proteins NPC1 or NPC2. We also discuss some potential therapeutic directions being suggested by recent research.
尼曼-匹克C型病（简称NPC）是一种儿童期疾病，表现为进行性神经退行性变，部分病例伴有肝脾肿大。在细胞水平上，该病是胆固醇和糖鞘脂（GSLs）等脂质向溶酶体样储存细胞器（LSOs）运输不当的结果，这些细胞器会被这些脂质填满。据信，无论是胆固醇还是GSLs的初始运输缺陷，最终都会导致这些LSOs出现交通堵塞。这不仅导致其他脂质的滞留，还导致跨膜蛋白的滞留，这些跨膜蛋白在正常细胞中与晚期内体（LE）短暂结合，在前往其他细胞目的地（如反式高尔基体网络（TGN））的途中。在这篇综述中，我们讨论了可能决定脂质和胆固醇细胞内行程的生物物理特性，以及在NPC1或NPC2蛋白存在缺陷的NPC细胞中这些行程是如何改变的。我们还讨论了近期研究所提出的一些潜在治疗方向。
