Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice
Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice
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DOI：
10.1038/nature04724
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发表时间：
2006-06-15
期刊：
影响因子：
64.8
通讯作者：
Mizushima, Noboru
中科院分区：
文献类型：
--
作者：
Hara, Taichi;Nakamura, Kenji;Mizushima, Noboru
自噬是一种细胞内整体降解过程，通过该过程，一部分细胞质被递送至溶酶体以被降解（1-4）。尽管自噬在许多生物体中的主要作用是适应饥饿，但自噬也被认为对于细胞质内容物的正常周转很重要，特别是在神经元等静止细胞中。自噬可能对许多神经退行性疾病的发展具有保护作用（5-8）。在这里，我们报告说，即使在没有任何疾病相关的突变蛋白的情况下，自噬的丧失也会导致神经退行性变。在神经细胞中特异性缺乏Atg 5（自噬相关5）的小鼠在运动功能中发展进行性缺陷，伴随着神经元中细胞质包涵体的积累。在Atg 5（-/-）细胞中，弥漫性的异常细胞内蛋白质积聚，然后形成聚集体和包涵体。这些结果表明，通过基础自噬持续清除弥漫性胞质蛋白对于防止异常蛋白的积累是重要的，异常蛋白的积累可以破坏神经功能并最终导致神经变性。
Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded(1-4). Although the primary role of autophagy in many organisms is in adaptation to starvation, autophagy is also thought to be important for normal turnover of cytoplasmic contents, particularly in quiescent cells such as neurons. Autophagy may have a protective role against the development of a number of neurodegenerative diseases(5-8). Here we report that loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins. Mice deficient for Atg5 (autophagy-related 5) specifically in neural cells develop progressive deficits in motor function that are accompanied by the accumulation of cytoplasmic inclusion bodies in neurons. In Atg5(-/-) cells, diffuse, abnormal intracellular proteins accumulate, and then form aggregates and inclusions. These results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.