Meyer Anja, Wree Andreas, Günther René, Holzmann Carsten, Schmitt Oliver, Rolfs Arndt, Witt Martin
Institute of Anatomy, University of Rostock, 18057 Rostock, Germany.
Institute of Medical Genetics, Rostock University Medical Center, 18057 Rostock, Germany.
Int J Mol Sci. 2017 Apr 6;18(4):777. doi: 10.3390/ijms18040777.
Niemann-Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of mutant mice compared with healthy controls (). Based on immunohistochemical evaluation of the olfactory epithelium, we analyzed the impact of neurodegeneration in the olfactory epithelium of mice and observed considerable loss of mature olfactory receptor neurons as well as an increased number of proliferating and apoptotic cells. Additionally, after administration of two different therapy approaches using either a combination of miglustat, 2-hydroxypropyl-β-cyclodextrin (HPβCD) and allopregnanolone or a monotherapy with HPβCD, we recorded a remarkable reduction of morphological damages in mice and an up to four-fold increase of proliferating cells within the olfactory epithelium. Numbers of mature olfactory receptor neurons doubled after both therapy approaches. Interestingly, we also observed therapy-induced alterations in treated controls. Thus, olfactory testing may provide useful information to monitor pharmacologic treatment approaches in human NPC1.
尼曼-匹克病C1型（NPC1）是一种致命的神经内脏溶酶体脂质贮积病。NPC1蛋白的突变影响胆固醇和糖鞘脂从晚期内体/溶酶体到内质网的稳态和转运，导致进行性神经退行性变。由于嗅觉障碍是许多神经退行性疾病最早出现的症状之一，我们聚焦于NPC1小鼠模型中嗅觉上皮的改变。先前的研究结果显示，与健康对照相比，突变小鼠的嗅觉系统存在严重的形态学和免疫组化改变（）。基于对嗅觉上皮的免疫组化评估，我们分析了神经退行性变对小鼠嗅觉上皮的影响，观察到成熟嗅觉受体神经元大量丢失，以及增殖和凋亡细胞数量增加。此外，在使用米格鲁司他、2-羟丙基-β-环糊精（HPβCD）和别孕烯醇酮联合用药或HPβCD单药治疗的两种不同治疗方法给药后，我们记录到小鼠的形态学损伤显著减少，嗅觉上皮内增殖细胞数量最多增加了四倍。两种治疗方法后成熟嗅觉受体神经元数量均增加了一倍。有趣的是，我们还在接受治疗的对照中观察到了治疗诱导的改变。因此，嗅觉测试可能为监测人类NPC1的药物治疗方法提供有用信息。
