Loss of autophagy in the central nervous system causes neurodegeneration in mice
Loss of autophagy in the central nervous system causes neurodegeneration in mice
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DOI：
10.1038/nature04723
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发表时间：
2006-06-15
期刊：
影响因子：
64.8
通讯作者：
Tanaka, Keiji
中科院分区：
文献类型：
--
作者：
Komatsu, Masaaki;Waguri, Satoshi;Tanaka, Keiji
蛋白质质量控制，特别是去除结构异常的蛋白质，在维持非分裂神经细胞的内稳态中起着重要作用(1)。除了泛素-蛋白酶体系统外，新出现的证据表明自噬在蛋白质质量控制过程中的重要性（2,3）。自噬是一种参与饥饿诱导和组成蛋白转化的大量蛋白质降解途径。然而，自噬在神经元中的确切作用尚不清楚。在这里，我们报道了Atg7（自噬相关基因7）的缺失导致神经退行性变，Atg7是自噬所必需的基因。我们发现中枢神经系统缺乏Atg7的小鼠表现出行为缺陷，包括异常的肢体握紧反射和协调运动的减少，并在出生28周内死亡。at7缺乏导致大脑和小脑皮层大量神经元丢失。值得注意的是，多泛素化蛋白在自噬缺陷的神经元中以包涵体的形式积累，包涵体的大小和数量随着年龄的增长而增加。然而，蛋白酶体功能未见明显改变。我们的研究结果表明，自噬对神经细胞的存活至关重要，自噬的损害与含泛素包涵体的神经退行性疾病的发病机制有关。
Protein quality-control, especially the removal of proteins with aberrant structures, has an important role in maintaining the homeostasis of non-dividing neural cells(1). In addition to the ubiquitin-proteasome system, emerging evidence points to the importance of autophagy-the bulk protein degradation pathway involved in starvation-induced and constitutive protein turnover-in the protein quality-control process(2,3). However, little is known about the precise roles of autophagy in neurons. Here we report that loss of Atg7 (autophagy-related 7), a gene essential for autophagy, leads to neurodegeneration. We found that mice lacking Atg7 specifically in the central nervous system showed behavioural defects, including abnormal limb-clasping reflexes and a reduction in coordinated movement, and died within 28 weeks of birth. Atg7 deficiency caused massive neuronal loss in the cerebral and cerebellar cortices. Notably, polyubiquitinated proteins accumulated in autophagy-deficient neurons as inclusion bodies, which increased in size and number with ageing. There was, however, no obvious alteration in proteasome function. Our results indicate that autophagy is essential for the survival of neural cells, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies.