Disruption and therapeutic rescue of autophagy in a human neuronal model of Niemann Pick type C1
Disruption and therapeutic rescue of autophagy in a human neuronal model of Niemann Pick type C1
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DOI：
10.1093/hmg/dds090
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发表时间：
2012-06-15
影响因子：
3.5
通讯作者：
Goldstein, Lawrence S. B.
中科院分区：
文献类型：
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作者：
Ordonez, M. Paulina;Roberts, Elizabeth A.;Goldstein, Lawrence S. B.
关于许多神经退行性疾病的一个未解决的问题是为什么神经元对无处不在的细胞过程中的缺陷特别敏感。一个例子是尼曼匹克C1型，由所有细胞中胆固醇运输的缺陷引起，但神经元优先受损。理解这种选择性失败受到难以从受影响患者中获得活的人类神经元的限制。为了解决这个问题，我们从人胚胎干细胞中产生了NPC 1功能降低的神经元，并使用它们来测试胆固醇处理缺陷导致神经元病理表型增强的假设。我们发现，人NPC 1神经元具有强烈的自噬自发激活，并且与之前在患者成纤维细胞中的报道相反，自噬进展的阻断导致线粒体清除缺陷。与成纤维细胞相比，NPC 1神经元中的线粒体片段化是异常严重的表型，导致线粒体蛋白异常积累。与预期相反，这些异常表型通过用自噬抑制剂3-甲基腺嘌呤治疗和通过用潜在的治疗性环糊精（其从溶酶体隔室动员胆固醇）治疗而被拯救。我们的研究结果表明，神经元对溶酶体胆固醇积累特别敏感，因为自噬破坏和碎片化线粒体的积累，从而为NPC 1疾病的有效药物开发确定了一条新途径。
An unresolved issue about many neurodegenerative diseases is why neurons are particularly sensitive to defects in ubiquitous cellular processes. One example is Niemann Pick type C1, caused by defects in cholesterol trafficking in all cells, but where neurons are preferentially damaged. Understanding this selective failure is limited by the difficulty in obtaining live human neurons from affected patients. To solve this problem, we generated neurons with decreased function of NPC1 from human embryonic stem cells and used them to test the hypothesis that defective cholesterol handling leads to enhanced pathological phenotypes in neurons. We found that human NPC1 neurons have strong spontaneous activation of autophagy, and, contrary to previous reports in patient fibroblasts, a block of autophagic progression leading to defective mitochondrial clearance. Mitochondrial fragmentation is an exceptionally severe phenotype in NPC1 neurons compared with fibroblasts, causing abnormal accumulation of mitochondrial proteins. Contrary to expectation, these abnormal phenotypes were rescued by treatment with the autophagy inhibitor 3-methyladenine and by treatment with the potential therapeutic cyclodextrin, which mobilizes cholesterol from the lysosomal compartment. Our findings suggest that neurons are especially sensitive to lysosomal cholesterol accumulation because of autophagy disruption and accumulation of fragmented mitochondria, thus defining a new route to effective drug development for NPC1 disease.