Coordinate Regulation of Mature Dopaminergic Axon Morphology by Macroautophagy and the PTEN Signaling Pathway

Keiichi Inoue, Joanne Rispoli, Lichuan Yang, David MacLeod, M. Flint Beal, Eric Klann, Asa Abeliovich

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1003845
JournalPLoS Genetics
Volume9
Issue number10
DOIs
StatePublished - Oct 2013

Fingerprint

Autophagy
dopamine
axons
Axons
Presynaptic Terminals
phenotype
turnover
neurons
degradation
protein
Dopaminergic Neurons
Dopamine
Neurons
protein degradation
organelles
Carisoprodol
Mesencephalon
phosphotransferases (kinases)
Organelles
Proteolysis

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Coordinate Regulation of Mature Dopaminergic Axon Morphology by Macroautophagy and the PTEN Signaling Pathway. / Inoue, Keiichi; Rispoli, Joanne; Yang, Lichuan; MacLeod, David; Beal, M. Flint; Klann, Eric; Abeliovich, Asa.

In: PLoS Genetics, Vol. 9, No. 10, e1003845, 10.2013.

Research output: Contribution to journalArticle

Inoue, Keiichi ; Rispoli, Joanne ; Yang, Lichuan ; MacLeod, David ; Beal, M. Flint ; Klann, Eric ; Abeliovich, Asa. / Coordinate Regulation of Mature Dopaminergic Axon Morphology by Macroautophagy and the PTEN Signaling Pathway. In: PLoS Genetics. 2013 ; Vol. 9, No. 10.
@article{b6e4f0a9cd4345d88ce7c6c34374eb2f,
title = "Coordinate Regulation of Mature Dopaminergic Axon Morphology by Macroautophagy and the PTEN Signaling Pathway",
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.",
author = "Keiichi Inoue and Joanne Rispoli and Lichuan Yang and David MacLeod and Beal, {M. Flint} and Eric Klann and Asa Abeliovich",
year = "2013",
month = "10",
doi = "10.1371/journal.pgen.1003845",
language = "English (US)",
volume = "9",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Coordinate Regulation of Mature Dopaminergic Axon Morphology by Macroautophagy and the PTEN Signaling Pathway

AU - Inoue, Keiichi

AU - Rispoli, Joanne

AU - Yang, Lichuan

AU - MacLeod, David

AU - Beal, M. Flint

AU - Klann, Eric

AU - Abeliovich, Asa

PY - 2013/10

Y1 - 2013/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84887305258&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887305258&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1003845

DO - 10.1371/journal.pgen.1003845

M3 - Article

VL - 9

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 10

M1 - e1003845

ER -