title: Activation of the unfolded protein response promotes axonal regeneration after peripheral nerve injury.
abstract: Although protein-folding stress at the endoplasmic reticulum (ER) is emerging as a driver of neuronal dysfunction in models of spinal cord injury and neurodegeneration, the contribution of this pathway to peripheral nerve damage remains poorly explored. Here we targeted the unfolded protein response (UPR), an adaptive reaction against ER stress, in mouse models of sciatic nerve injury and found that ablation of the transcription factor XBP1, but not ATF4, significantly delay locomotor recovery. XBP1 deficiency led to decreased macrophage recruitment, a reduction in myelin removal and axonal regeneration. Conversely, overexpression of XBP1s in the nervous system in transgenic mice enhanced locomotor recovery after sciatic nerve crush, associated to an improvement in key pro-regenerative events. To assess the therapeutic potential of UPR manipulation to axonal regeneration, we locally delivered XBP1s or an shRNA targeting this transcription factor to sensory neurons of the dorsal root ganglia using a gene therapy approach and found an enhancement or reduction of axonal regeneration in vivo, respectively. Our results demonstrate a functional role of specific components of the ER proteostasis network in the cellular changes associated to regeneration and functional recovery after peripheral nerve injury.
authors.affiliation: Geroscience Center for Brain Health and Metabolism, Santiago, Chile.|Millenium Nucleus for Regenerative Biology, Faculty of Biology, Pontificia Universidad Católica de Chile, Santiago, Chile.|Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.|Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, University of Chile, Santiago, Chile.
authors.forename: Maritza
authors.initials: M
authors.lastname: Oñate
authors.affiliation: Geroscience Center for Brain Health and Metabolism, Santiago, Chile.|Millenium Nucleus for Regenerative Biology, Faculty of Biology, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Catenaccio
authors.affiliation: Geroscience Center for Brain Health and Metabolism, Santiago, Chile.|Millenium Nucleus for Regenerative Biology, Faculty of Biology, Pontificia Universidad Católica de Chile, Santiago, Chile.|Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.|Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, University of Chile, Santiago, Chile.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Martínez
authors.affiliation: Department of Molecular Biology, Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Armentano
authors.affiliation: Department of Molecular Biology, Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Parsons
authors.affiliation: Centro de Estudios Científicos, Valdivia, Chile.
authors.forename: Bredford
authors.initials: B
authors.lastname: Kerr
authors.affiliation: Geroscience Center for Brain Health and Metabolism, Santiago, Chile.|Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.|Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, University of Chile, Santiago, Chile.|Department of Immunology and Infectious diseases, Harvard School of Public Health, Boston MA, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
authors.affiliation: Geroscience Center for Brain Health and Metabolism, Santiago, Chile.|Millenium Nucleus for Regenerative Biology, Faculty of Biology, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Court
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000502:physiology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D015870:Gene Expression; D008124:Locomotion; D008264:Macrophages / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009416:Nerve Regeneration; D059348:Peripheral Nerve Injuries / Q000503:physiopathology*; D020127:Recovery of Function; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism / Q000503:physiopathology*; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D051701:Activating Transcription Factor 4