Molecular, anatomical, and biochemical events associated with neurodegeneration in mice with Niemann-Pick type C disease
Molecular, anatomical, and biochemical events associated with neurodegeneration in mice with Niemann-Pick type C disease
复制标题
DOI：
10.1093/jnen/64.4.323
复制
发表时间：
2005-04-01
影响因子：
3.2
通讯作者：
Dietschy, JM
中科院分区：
文献类型：
--
作者：
Li, H;Repa, JJ;Dietschy, JM
在尼曼-皮克C型（NPC）疾病中，与载脂蛋白e或载脂蛋白ob（100）相关的胆固醇被包括中枢神经系统在内的所有组织的细胞通过网格蛋白包被的小坑吸收，并被困在晚期内体和溶酶体中。本研究定义了神经细胞死亡后发生的功能、生化和分子事件。在NPC1突变纯合的小鼠中，神经肌肉功能障碍开始于5周龄，死亡发生于13周龄。胆固醇在身体的每一个组织中积累。小脑浦肯野细胞损失始于3 - 4周龄，到11周龄时几乎完全消失。这种小脑神经退行性变与caspase 1、caspase 3、NPC2、LipA、apoE、apoD、胶质纤维酸性蛋白和肿瘤坏死因子α mRNA水平升高有关，但与LXR核受体的大多数靶基因无关。apoER2的水平显著降低。这些研究表明，NPC2和LipA的代偿性增加试图克服由突变引起的生理缺陷。然而，神经退行性变是通过神经胶质细胞的活化、apoE和apoD合成的增加以及中枢神经系统胆固醇转换的增加而发生的。
In Niemann-Pick type C (NPC) disease, cholesterol associated with either apoE or apoB(100) is taken up by cells in all tissues, including the central nervous system, through clathrin-coated pits and becomes trapped in late endosomes and lysosomes. This study defines the functional, biochemical, and molecular events that ensue as nerve cell death occurs. In mice homozygous for a mutation in NPC1, neuromuscular dysfunction begins at 5 weeks and death occurs at 13 weeks of age. Cholesterol accumulates in every tissue in the body. Purkinje cell loss in the cerebellum begins at 3 to 4 weeks of age and is nearly complete by 11 weeks. This neurodegeneration in the cerebellum is associated with increases in the levels of mRNA for caspase 1, caspase 3, NPC2, LipA, apoE, apoD, glial fibrillary acidic protein, and tumor necrosis factor-alpha, but not for most target genes of the LXR nuclear receptors. The level for apoER2 is significantly reduced. These studies show there is a compensatory increase in NPC2 and LipA in an attempt to overcome the physiological defect caused by the mutation. Nevertheless, neurodegeneration proceeds utilizing apoptosis with activation of glial cells, increased apoE and apoD synthesis, and increased cholesterol turnover across the CNS.