Mizushima Noboru
Department of Physiology and Cell Biology, Tokyo Medical and Dental University.
Rinsho Shinkeigaku. 2006 Nov;46(11):885-6.
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 quality control, particularly in quiescent cells such as neurons. Atg5 -/- 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. 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 generation of aggregates and inclusions. This study emphasizes that basal autophagy is important even in individuals who do not express neurodegenerative disease-associated mutant proteins. Further, the primary targets of autophagy are diffused cytosolic proteins, not protein aggregates themselves. These data suggest that basal autophagy has a critical role in intracellular protein quality control under normal conditions, which is independent of the role of induced autophagy as an adaptation to starvation.
自噬是一种细胞内的大量降解过程，通过该过程，一部分细胞质被输送到溶酶体进行降解。在许多生物体中，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质量控制也很重要，特别是在诸如神经元等静止细胞中。Atg5基因敲除小鼠出生后不久死亡，至少部分原因是营养缺乏。这些小鼠的神经元和肝细胞中还表现出蛋白质聚集体的细胞内积累。神经细胞特异性Atg5缺陷小鼠，即Atg5(flox/flox); Nestin-Cre小鼠，表现出运动功能的进行性缺陷和一些神经细胞的退化。在自噬缺陷细胞中，异常蛋白质会出现弥漫性积累，随后形成聚集体和包涵体。这项研究强调，基础自噬即使在不表达神经退行性疾病相关突变蛋白的个体中也很重要。此外，自噬的主要靶点是弥漫性的胞质蛋白，而不是蛋白质聚集体本身。这些数据表明，基础自噬在正常条件下的细胞内蛋白质质量控制中起关键作用，这与诱导自噬作为适应饥饿的作用无关。
