Hara Taichi, Nakamura Kenji, Matsui Makoto, Yamamoto Akitsugu, Nakahara Yohko, Suzuki-Migishima Rika, Yokoyama Minesuke, Mishima Kenji, Saito Ichiro, Okano Hideyuki, Mizushima Noboru
Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan.
Nature. 2006 Jun 15;441(7095):885-9. doi: 10.1038/nature04724. Epub 2006 Apr 19.
Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded. 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. 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.
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。尽管自噬在许多生物体中的主要作用是适应饥饿，但自噬也被认为对细胞质内容物的正常更新很重要，特别是在诸如神经元等静止细胞中。自噬可能对多种神经退行性疾病的发展具有保护作用。在此我们报告，即使在没有任何与疾病相关的突变蛋白的情况下，自噬的缺失也会导致神经退行性变。特异性缺失神经细胞中Atg5（自噬相关5）的小鼠会出现进行性运动功能缺陷，并伴有神经元中细胞质包涵体的积累。在Atg5基因敲除细胞中，弥漫性的异常细胞内蛋白会积累，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很重要，而异常蛋白的积累会破坏神经功能并最终导致神经退行性变。
