Department of Pediatrics, University of California-San Diego, La Jolla, CA, USA.
Autophagy. 2012 Jul 1;8(7):1157-8. doi: 10.4161/auto.20668. Epub 2012 May 31.
Although traditionally regarded as a cellular adaptive process triggered by nutrient deprivation, autophagy in neurons appears to provide an important neuroprotective mechanism. Neurons in the brain are protected from starvation, and neuronal autophagy serves a critical role in the turnover of abnormal proteins and damaged organelles. As post-mitotic, highly polarized cells with active protein trafficking, neurons rely heavily on an efficient autophagic pathway. Using human embryonic stem cell-derived neurons engineered to mimic the cholesterol lysosomal storage disease Niemann Pick type C1 (NPC1), we have shown that excessive activation and impaired progression of the autophagic pathway conspire to cause abnormal mitochondrial clearance. Defective mitophagy is exceptionally severe in human NPC1 neurons, as compared with patient fibroblasts, and may explain the selective neuronal failure observed in NPC1 and related neurodegenerative disorders.
尽管自噬传统上被认为是一种由营养缺乏触发的细胞适应性过程，但神经元中的自噬似乎提供了一种重要的神经保护机制。大脑中的神经元可以免受饥饿的影响，神经元自噬在异常蛋白质和受损细胞器的周转中起着关键作用。作为有丝分裂后、高度极化且具有活跃蛋白质运输的细胞，神经元严重依赖有效的自噬途径。我们使用经过基因工程改造的人胚胎干细胞衍生神经元来模拟胆固醇溶酶体贮积病尼曼-皮克 C1 型（NPC1），结果表明，自噬途径的过度激活和进展受损会导致异常线粒体清除。与患者成纤维细胞相比，人 NPC1 神经元中的缺陷线粒体自噬异常严重，这可能解释了 NPC1 和相关神经退行性疾病中观察到的选择性神经元衰竭。
