Oxidative stress induces overgrowth of the Drosophila neuromuscular junction

Valerie J. Milton; Kate Gowers; Helen E. Jarrett; Salma Chalak; Laura Briggs; Iain M. Robinson; Sean T. Sweeney

doi:10.1073/pnas.1014511108

Oxidative stress induces overgrowth of the Drosophila neuromuscular junction

Valerie J. Milton, Kate Gowers, Helen E. Jarrett, Salma Chalak, Laura Briggs, Iain M. Robinson, Sean T. Sweeney

Biology

Research output: Contribution to journal › Article › peer-review

Abstract

Synaptic terminals are known to expand and contract throughout an animal's life. The physiological constraints and demands that regulate appropriate synaptic growth and connectivity are currently poorly understood. In previous work, we identified a Drosophila model of lysosomal storage disease (LSD), spinster (spin), with larval neuromuscular synapse overgrowth. Here we identify a reactive oxygen species (ROS) burden in spin that may be attributable to previously identified lipofuscin deposition and lysosomal dysfunction, a cellular hallmark of LSD. Reducing ROS in spin mutants rescues synaptic overgrowth and electrophysiological deficits. Synapse overgrowth was also observed in mutants defective for protection from ROS and animals subjected to excessive ROS. ROS are known to stimulate JNK and fos signaling. Furthermore, JNK and fos in turn are known potent activators of synapse growth and function. Inhibiting JNK and fos activity in spin rescues synapse overgrowth and electrophysiological deficits. Similarly, inhibiting JNK, fos, and jun activity in animals with excessive oxidative stress rescues the overgrowth phenotype. These data suggest that ROS, via activation of the JNK signaling pathway, are a major regulator of synapse overgrowth. In LSD, increased autophagy contributes to lysosomal storage and, presumably, elevated levels of oxidative stress. In support of this suggestion, we report here that impaired autophagy function reverses synaptic overgrowth in spin. Our data describe a previously unexplored link between oxidative stress and synapse overgrowth via the JNK signaling pathway.

Original language	English
Pages (from-to)	17521-17526
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	108
Issue number	42
DOIs	https://doi.org/10.1073/pnas.1014511108
Publication status	Published - 18 Oct 2011

Keywords

REGULATES SYNAPTIC GROWTH
PROGRAMMED CELL-DEATH
SUPEROXIDE-DISMUTASE
SIGNAL-TRANSDUCTION
LIFE-SPAN
AUTOPHAGY
PLASTICITY
PROTEIN
APOPTOSIS
PATHWAY

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10.1073/pnas.1014511108

http://www.pnas.org/content/108/42/17521

Cite this

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title = "Oxidative stress induces overgrowth of the Drosophila neuromuscular junction",

abstract = "Synaptic terminals are known to expand and contract throughout an animal's life. The physiological constraints and demands that regulate appropriate synaptic growth and connectivity are currently poorly understood. In previous work, we identified a Drosophila model of lysosomal storage disease (LSD), spinster (spin), with larval neuromuscular synapse overgrowth. Here we identify a reactive oxygen species (ROS) burden in spin that may be attributable to previously identified lipofuscin deposition and lysosomal dysfunction, a cellular hallmark of LSD. Reducing ROS in spin mutants rescues synaptic overgrowth and electrophysiological deficits. Synapse overgrowth was also observed in mutants defective for protection from ROS and animals subjected to excessive ROS. ROS are known to stimulate JNK and fos signaling. Furthermore, JNK and fos in turn are known potent activators of synapse growth and function. Inhibiting JNK and fos activity in spin rescues synapse overgrowth and electrophysiological deficits. Similarly, inhibiting JNK, fos, and jun activity in animals with excessive oxidative stress rescues the overgrowth phenotype. These data suggest that ROS, via activation of the JNK signaling pathway, are a major regulator of synapse overgrowth. In LSD, increased autophagy contributes to lysosomal storage and, presumably, elevated levels of oxidative stress. In support of this suggestion, we report here that impaired autophagy function reverses synaptic overgrowth in spin. Our data describe a previously unexplored link between oxidative stress and synapse overgrowth via the JNK signaling pathway.",

keywords = "REGULATES SYNAPTIC GROWTH, PROGRAMMED CELL-DEATH, SUPEROXIDE-DISMUTASE, SIGNAL-TRANSDUCTION, LIFE-SPAN, AUTOPHAGY, PLASTICITY, PROTEIN, APOPTOSIS, PATHWAY",

author = "Milton, {Valerie J.} and Kate Gowers and Jarrett, {Helen E.} and Salma Chalak and Laura Briggs and Robinson, {Iain M.} and Sweeney, {Sean T.}",

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T1 - Oxidative stress induces overgrowth of the Drosophila neuromuscular junction

AU - Milton, Valerie J.

AU - Gowers, Kate

AU - Jarrett, Helen E.

AU - Chalak, Salma

AU - Briggs, Laura

AU - Robinson, Iain M.

AU - Sweeney, Sean T.

PY - 2011/10/18

Y1 - 2011/10/18

N2 - Synaptic terminals are known to expand and contract throughout an animal's life. The physiological constraints and demands that regulate appropriate synaptic growth and connectivity are currently poorly understood. In previous work, we identified a Drosophila model of lysosomal storage disease (LSD), spinster (spin), with larval neuromuscular synapse overgrowth. Here we identify a reactive oxygen species (ROS) burden in spin that may be attributable to previously identified lipofuscin deposition and lysosomal dysfunction, a cellular hallmark of LSD. Reducing ROS in spin mutants rescues synaptic overgrowth and electrophysiological deficits. Synapse overgrowth was also observed in mutants defective for protection from ROS and animals subjected to excessive ROS. ROS are known to stimulate JNK and fos signaling. Furthermore, JNK and fos in turn are known potent activators of synapse growth and function. Inhibiting JNK and fos activity in spin rescues synapse overgrowth and electrophysiological deficits. Similarly, inhibiting JNK, fos, and jun activity in animals with excessive oxidative stress rescues the overgrowth phenotype. These data suggest that ROS, via activation of the JNK signaling pathway, are a major regulator of synapse overgrowth. In LSD, increased autophagy contributes to lysosomal storage and, presumably, elevated levels of oxidative stress. In support of this suggestion, we report here that impaired autophagy function reverses synaptic overgrowth in spin. Our data describe a previously unexplored link between oxidative stress and synapse overgrowth via the JNK signaling pathway.

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KW - PROGRAMMED CELL-DEATH

KW - SUPEROXIDE-DISMUTASE

KW - SIGNAL-TRANSDUCTION

KW - LIFE-SPAN

KW - AUTOPHAGY

KW - PLASTICITY

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KW - APOPTOSIS

KW - PATHWAY

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DO - 10.1073/pnas.1014511108

M3 - Article

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EP - 17526

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 42

ER -

Oxidative stress induces overgrowth of the Drosophila neuromuscular junction

Abstract

Keywords

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