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.
Highlights
Macroautophagy is an intracellular protein degradation mechanism that engulfs cytoplasmic constituents and entire organelles within double-membrane vesicles and delivers these to lysosomes [1,2]
We show that Atg7, an essential component of macroautophagy, regulates mature dopaminergic axon terminal morphology in coordination with the well-described role of the phosphatidylinositide 3-kinase (PI3K) pathway
Atg7 and Pten double deficiency leads to further axon terminal enlargement, suggesting that Atg7 deficiency unmasks the impact of PI3K/mTOR pathway on mature dopaminergic axon terminals
Summary
Macroautophagy is an intracellular protein degradation mechanism that engulfs cytoplasmic constituents and entire organelles within double-membrane vesicles and delivers these to lysosomes [1,2]. Genetic deletion of the essential macroautophagy components Atg or Atg, during mouse central nervous system (CNS) development, leads to neuronal loss and inclusion formation [3,4]. Atg deficiency confined to cerebellar Purkinje cells leads to dystrophic axons and subsequent cell death within several weeks [5,6]. In addition to pathological roles, protein degradation pathways may play important physiological functions in neurons. Several studies have underscored the role of cytoplasmic protein degradation through the ubiquitin-proteosome system (UPS) in the regulation of neuronal morphology and function [7]. The role of macroautophagy in this context is unclear
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