Coordinate Regulation of Mature Dopaminergic Axon Morphology by Macroautophagy and the PTEN Signaling Pathway |
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| Authors: | Keiichi Inoue Joanne Rispoli Lichuan Yang David MacLeod M Flint Beal Eric Klann Asa Abeliovich |
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| Institution: | 1.Departments of Pathology and Neurology, Taub Institute, Columbia University Medical Center, New York, New York, United States of America;2.Department of Neurology and Neuroscience, Weill Cornell Medical College of Cornell University, New York, New York, United States of America;3.Center for Neural Science, New York University, New York, New York, United States of America;Stanford University School of Medicine, United States of America |
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| Abstract: | 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. |
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