Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556 5670, USA.
Neurotherapeutics. 2013 Oct;10(4):688-97. doi: 10.1007/s13311-013-0217-2.
Niemann-Pick type C disease (NPC) is a devastating, recessive, inherited disorder that causes accumulation of cholesterol and other lipids in late endosomes and lysosomes. Mutations in 2 genes, NPC1 and NPC2, are responsible for the disease, which affects about 1 in 120,000 live births. About 95% of patients have mutations in NPC1, a large polytopic membrane protein that is normally found in late endosomes. More than 200 missense mutations in NPC1 have been found in NPC patients. The disease is progressive, typically leading to death before the age of 20 years, although some affected individuals live well into adulthood. The disease affects peripheral organs, including the liver, spleen, and lungs, but the most severe symptoms are associated with neurological disease. There are some palliative treatments that slow progression of NPC disease. Recently, it was found that histone deacetylase (HDAC) inhibitors that are effective against HDACs 1, 2, and 3 can reduce the cholesterol accumulation in fibroblasts derived from NPC patients with mutations in NPC1. One example is vorinostat. As vorinostat is a Food and Drug Administration-approved drug for treatment of cutaneous T-cell lymphoma, this opens up the possibility that HDAC inhibitors could be repurposed for treatment of this rare disease. The mechanism of action of the HDAC inhibitors requires further study, but these drugs increase the level of the NPC1 protein. This may be due to post-translational stabilization of the NPC1 protein, allowing it to be transported out of the endoplasmic reticulum.
尼曼-匹克 C 型病（NPC）是一种破坏性的、隐性的、遗传性疾病，导致胆固醇和其他脂质在内体晚期和溶酶体中积累。2 个基因 NPC1 和 NPC2 的突变导致该疾病，其发病率约为每 12 万活产儿中有 1 例。大约 95%的患者 NPC1 基因突变，NPC1 是一种大型多域膜蛋白，通常存在于晚期内体中。在 NPC 患者中发现了超过 200 种 NPC1 的错义突变。该疾病呈进行性发展，通常在 20 岁之前导致死亡，尽管一些受影响的个体能很好地进入成年期。该疾病影响外周器官，包括肝脏、脾脏和肺部，但最严重的症状与神经疾病有关。有一些姑息治疗可以减缓 NPC 疾病的进展。最近发现，对 HDAC1、2 和 3 有效的组蛋白去乙酰化酶（HDAC）抑制剂可以减少 NPC1 突变 NPC 患者成纤维细胞中的胆固醇积累。一个例子是伏立诺他。由于伏立诺他是美国食品和药物管理局批准的用于治疗皮肤 T 细胞淋巴瘤的药物，这为 HDAC 抑制剂可能被重新用于治疗这种罕见疾病开辟了可能性。HDAC 抑制剂的作用机制需要进一步研究，但这些药物增加了 NPC1 蛋白的水平。这可能是由于 NPC1 蛋白的翻译后稳定，使其能够从内质网中运输出来。
