Intracellular quality control by autophagy: How does autophagy prevent neurodegeneration?
Intracellular quality control by autophagy: How does autophagy prevent neurodegeneration?
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DOI：
10.4161/auto.2945
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发表时间：
2006-10-01
期刊：
影响因子：
13.3
通讯作者：
Hara, Taichi
中科院分区：
文献类型：
--
作者：
Mizushima, Noboru;Hara, Taichi
自噬是一种细胞内的整体降解过程，通过该过程，一部分细胞质被递送到溶酶体以被降解。在许多生物中，自噬的主要作用是适应饥饿。然而，我们发现自噬对于细胞内蛋白质质量控制也很重要。Atq 5（-/-）小鼠出生后不久死亡，至少部分原因是营养缺乏。这些小鼠还表现出神经元和肝细胞中蛋白质聚集体的细胞内积累。我们现在报告神经细胞特异性Atg 5缺陷小鼠的产生。Atg 5（flox/flox）;Nestin-Cre小鼠显示出运动功能的进行性缺陷和一些神经细胞的退化。在自噬缺陷的细胞中，发生异常蛋白质的扩散积累，随后产生聚集体和内含物。这项研究强调了一点，即即使在不表达神经退行性疾病相关突变蛋白的个体中，基础自噬也很重要。此外，自噬的主要目标是弥漫性胞质蛋白，而不是蛋白质聚集体本身。
Autophagy is an intracellular bulk degradation process, through which a portion of cytoplasm is delivered to lysosomes to be degraded. In many organisms, the primary role of autophagy is adaptation to starvation. However, we have found that autophagy is also important for intracellular protein quality control. Atq5(-/-) mice die shortly after birth due, at least in part, to nutrient deficiency. These mice also exhibit an intracellular accumulation of protein aggregates in neurons and hepatocytes. We now report the generation of neural cell-specific Atg5-deficient mice. Atg5(flox/flox);Nestin-Cre mice show progressive deficits in motor function and degeneration of some neural cells. In autophagy-deficient cells, diffuse accumulation of abnormal proteins occurs, followed by the generation of aggregates and inclusions. This study emphasizes the point that basal autophagy is important even in individuals who do not express neurodegenerative disease-associated mutant proteins. Furthermore, the primary targets of autophagy are diffuse cytosolic proteins, not protein aggregates themselves.