title: Functional Role of the Disulfide Isomerase ERp57 in Axonal Regeneration.
abstract: ERp57 (also known as grp58 and PDIA3) is a protein disulfide isomerase that catalyzes disulfide bonds formation of glycoproteins as part of the calnexin and calreticulin cycle. ERp57 is markedly upregulated in most common neurodegenerative diseases downstream of the endoplasmic reticulum (ER) stress response. Despite accumulating correlative evidence supporting a neuroprotective role of ERp57, the contribution of this foldase to the physiology of the nervous system remains unknown. Here we developed a transgenic mouse model that overexpresses ERp57 in the nervous system under the control of the prion promoter. We analyzed the susceptibility of ERp57 transgenic mice to undergo neurodegeneration. Unexpectedly, ERp57 overexpression did not affect dopaminergic neuron loss and striatal denervation after injection of a Parkinson's disease-inducing neurotoxin. In sharp contrast, ERp57 transgenic animals presented enhanced locomotor recovery after mechanical injury to the sciatic nerve. These protective effects were associated with enhanced myelin removal, macrophage infiltration and axonal regeneration. Our results suggest that ERp57 specifically contributes to peripheral nerve regeneration, whereas its activity is dispensable for the survival of a specific neuronal population of the central nervous system. These results demonstrate for the first time a functional role of a component of the ER proteostasis network in peripheral nerve regeneration.
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors.forename: Valentina
authors.initials: V
authors.lastname: Castillo
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile; Millenium Nucleus for Regenerative Biology, Faculty of Biology, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Maritza
authors.initials: M
authors.lastname: Oñate
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors.forename: Ute
authors.initials: U
authors.lastname: Woehlbier
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors.forename: Pablo
authors.initials: P
authors.lastname: Rozas
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors.forename: Catherine
authors.initials: C
authors.lastname: Andreu
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors.forename: Danilo
authors.initials: D
authors.lastname: Medinas
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: Valdés
authors.affiliation: Program of Immunology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Osorio
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Mercado
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Neurounion Biomedical Foundation, CENPAR, Santiago, Chile.
authors.forename: René L
authors.initials: RL
authors.lastname: Vidal
authors.affiliation: Centro de Estudios Científicos, Valdivia, Chile.
authors.forename: Bredford
authors.initials: B
authors.lastname: Kerr
authors.affiliation: 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
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile; Department of Immunology and Infectious diseases, Harvard School of Public Health, Boston MA, United States of America.
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003342:Corpus Striatum / Q000378:metabolism; D003714:Denervation; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009043:Motor Activity / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D009424:Nervous System Physiological Phenomena; D016627:Oxidopamine / Q000494:pharmacology; D059348:Peripheral Nerve Injuries / Q000235:genetics / Q000503:physiopathology / Q000534:rehabilitation; D019704:Protein Disulfide-Isomerases / Q000235:genetics* / Q000378:metabolism*; D012038:Regeneration
chemical_list: D016627:Oxidopamine; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human