Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany.
Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, 18147 Rostock, Germany.
Int J Mol Sci. 2021 Jan 12;22(2):710. doi: 10.3390/ijms22020710.
The lysosomal storage disorders Niemann-Pick disease Type C1 (NPC1) and Type C2 (NPC2) are rare diseases caused by mutations in the or gene. Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY). Consequently, mutations in one of the two proteins lead to the accumulation of unesterified cholesterol and glycosphingolipids in LE/LY, displaying a disease hallmark. A total of 95% of cases are due to a deficiency of NPC1 and only 5% are caused by NPC2 deficiency. Clinical manifestations include neurological symptoms and systemic symptoms, such as hepatosplenomegaly and pulmonary manifestations, the latter being particularly pronounced in NPC2 patients. NPC1 and NPC2 are rare diseases with the described neurovisceral clinical picture, but studies with human primary patient-derived neurons and hepatocytes are hardly feasible. Obviously, induced pluripotent stem cells (iPSCs) and their derivatives are an excellent alternative for indispensable studies with these affected cell types to study the multisystemic disease NPC1. Here, we present a review focusing on studies that have used iPSCs for disease modeling and drug discovery in NPC1 and draw a comparison to commonly used NPC1 models.
溶酶体贮积症尼曼-匹克病 C1 型（NPC1）和 C2 型（NPC2）是由 或 基因突变引起的罕见疾病。NPC1 和 NPC2 均为负责胆固醇从晚期内体和溶酶体（LE/LY）中排出的蛋白质。因此，两种蛋白之一的突变导致未酯化胆固醇和糖鞘脂在 LE/LY 中的积累，显示出疾病的特征。95%的病例是由于 NPC1 缺乏引起的，只有 5%是由 NPC2 缺乏引起的。临床表现包括神经症状和全身症状，如肝脾肿大和肺部表现，后者在 NPC2 患者中尤为明显。NPC1 和 NPC2 是具有描述性神经内脏临床特征的罕见疾病，但使用人原代患者来源神经元和肝细胞进行研究几乎是不可行的。显然，诱导多能干细胞（iPSCs）及其衍生物是研究 NPC1 多系统疾病时替代这些受影响细胞类型进行不可或缺研究的绝佳选择。在这里，我们将重点介绍使用 iPSCs 进行 NPC1 疾病建模和药物发现的研究，并与常用的 NPC1 模型进行比较。
