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.
authors: Department of Biology and Hull York Medical School, University of York, York YO10 5DD, United Kingdom.
authors: Valerie J
authors: VJ
authors: Milton
authors: Helen E
authors: HE
authors: Jarrett
authors: Kate
authors: K
authors: Gowers
authors: Salma
authors: S
authors: Chalak
authors: Laura
authors: L
authors: Briggs
authors: Iain M
authors: IM
authors: Robinson
authors: Sean T
authors: ST
authors: Sweeney
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D017344:Genes, Insect; D020140:Lysosomal Storage Diseases, Nervous System / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008959:Models, Neurological; D009154:Mutation; D009469:Neuromuscular Junction / Q000254:growth & development* / Q000378:metabolism*; D018384:Oxidative Stress; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D018808:Transcription Factor AP-1; C429164:spin protein, Drosophila