Departments of Pathology and Neurology, Taub Institute, Columbia University Medical Center, New York, New York, United States of America.
PLoS Genet. 2013;9(10):e1003845. doi: 10.1371/journal.pgen.1003845. Epub 2013 Oct 3.
Macroautophagy is a conserved mechanism for the bulk degradation of proteins and organelles. Pathological studies have implicated defective macroautophagy in neurodegeneration, but physiological functions of macroautophagy in adult neurons remain unclear. Here we show that Atg7, an essential macroautophagy component, regulates dopaminergic axon terminal morphology. Mature Atg7-deficient midbrain dopamine (DA) neurons harbored selectively enlarged axonal terminals. This contrasted with the phenotype of DA neurons deficient in Pten - a key negative regulator of the mTOR kinase signaling pathway and neuron size - that displayed enlarged soma but unaltered axon terminals. Surprisingly, concomitant deficiency of both Atg7 and Pten led to a dramatic enhancement of axon terminal enlargement relative to Atg7 deletion alone. Similar genetic interactions between Atg7 and Pten were observed in the context of DA turnover and DA-dependent locomotor behaviors. These data suggest a model for morphological regulation of mature dopaminergic axon terminals whereby the impact of mTOR pathway is suppressed by macroautophagy.
自噬是一种用于批量降解蛋白质和细胞器的保守机制。病理学研究表明，自噬缺陷与神经退行性变有关，但成年神经元中的自噬生理功能仍不清楚。在这里，我们发现自噬的必需成分 Atg7 调节多巴胺能轴突末梢的形态。成熟的 Atg7 缺陷型中脑多巴胺（DA）神经元选择性地具有增大的轴突末梢。这与 Pten 缺陷型 DA 神经元的表型形成对比，Pten 是 mTOR 激酶信号通路的关键负调控因子，并且与神经元大小有关，Pten 缺陷型 DA 神经元显示出增大的胞体但不变的轴突末梢。令人惊讶的是，Atg7 和 Pten 的同时缺失导致相对于单独缺失 Atg7，轴突末梢的增大显著增强。在 DA 周转率和 DA 依赖性运动行为的背景下，观察到 Atg7 和 Pten 之间存在类似的遗传相互作用。这些数据表明了成熟的多巴胺能轴突末梢形态调节的模型，其中 mTOR 通路的影响被自噬所抑制。
