title: Diapause formation and downregulation of insulin-like signaling via DAF-16/FOXO delays axonal degeneration and neuronal loss.
abstract: Axonal degeneration is a key event in the pathogenesis of neurodegenerative conditions. We show here that mec-4d triggered axonal degeneration of Caenorhabditis elegans neurons and mammalian axons share mechanistical similarities, as both are rescued by inhibition of calcium increase, mitochondrial dysfunction, and NMNAT overexpression. We then explore whether reactive oxygen species (ROS) participate in axonal degeneration and neuronal demise. C. elegans dauers have enhanced anti-ROS systems, and dauer mec-4d worms are completely protected from axonal degeneration and neuronal loss. Mechanistically, downregulation of the Insulin/IGF-1-like signaling (IIS) pathway protects neurons from degenerating in a DAF-16/FOXO-dependent manner and is related to superoxide dismutase and catalase-increased expression. Caloric restriction and systemic antioxidant treatment, which decrease oxidative damage, protect C. elegans axons from mec-4d-mediated degeneration and delay Wallerian degeneration in mice. In summary, we show that the IIS pathway is essential in maintaining neuronal homeostasis under pro-degenerative stimuli and identify ROS as a key intermediate of neuronal degeneration in vivo. Since axonal degeneration represents an early pathological event in neurodegeneration, our work identifies potential targets for therapeutic intervention in several conditions characterized by axonal loss and functional impairment.
authors.affiliation: Department of Cellular Biology, Faculty of Biology, Pontifical Catholic University of Chile, Santiago, Chile.
authors.forename: Andrea
authors.initials: A
authors.lastname: Calixto
authors.forename: Juan S
authors.initials: JS
authors.lastname: Jara
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Court
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002374:Catalase; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D002118:Calcium; D002374:Catalase; D051858:Forkhead Transcription Factors; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D008565:Membrane Proteins; D009612:Nicotinamide-Nucleotide Adenylyltransferase; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D014157:Transcription Factors; C115871:Mec-4 protein, C elegans; C108831:daf-16 protein, C elegans; C510972:Nmnat1 protein, mouse