title: RTN3 Is a Novel Cold-Induced Protein and Mediates Neuroprotective Effects of RBM3.
abstract: Cooling and hypothermia are profoundly neuroprotective, mediated, at least in part, by the cold shock protein, RBM3. However, the neuroprotective effector proteins induced by RBM3 and the mechanisms by which mRNAs encoding cold shock proteins escape cooling-induced translational repression are unknown. Here, we show that cooling induces reprogramming of the translatome, including the upregulation of a new cold shock protein, RTN3, a reticulon protein implicated in synapse formation. We report that this has two mechanistic components. Thus, RTN3 both evades cooling-induced translational elongation repression and is also bound by RBM3, which drives the increased expression of RTN3. In mice, knockdown of RTN3 expression eliminated cooling-induced neuroprotection. However, lentivirally mediated RTN3 overexpression prevented synaptic loss and cognitive deficits in a mouse model of neurodegeneration, downstream and independently of RBM3. We conclude that RTN3 expression is a mediator of RBM3-induced neuroprotection, controlled by novel mechanisms of escape from translational inhibition on cooling.
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Amandine
authors.initials: A
authors.lastname: Bastide
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, UK.
authors.forename: Diego
authors.initials: D
authors.lastname: Peretti
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: John R P
authors.initials: JR
authors.lastname: Knight
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Stefano
authors.initials: S
authors.lastname: Grosso
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Ruth V
authors.initials: RV
authors.lastname: Spriggs
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Xavier
authors.initials: X
authors.lastname: Pichon
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sbarrato
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Roobol
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Jo
authors.initials: J
authors.lastname: Roobol
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Davide
authors.initials: D
authors.lastname: Vito
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Bushell
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Tobias
authors.initials: T
authors.lastname: von der Haar
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK. Electronic address: c.m.smales@kent.ac.uk.
authors.forename: C Mark
authors.initials: CM
authors.lastname: Smales
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, UK. Electronic address: gm522@cam.ac.uk.
authors.forename: Giovanna R
authors.initials: GR
authors.lastname: Mallucci
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK. Electronic address: aew5@le.ac.uk.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Willis
mesh_terms: D000818:Animals; D057773:Cold Shock Proteins and Peptides / Q000235:genetics* / Q000378:metabolism; D003080:Cold Temperature; D058639:Cold-Shock Response / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D057773:Cold Shock Proteins and Peptides; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D016601:RNA-Binding Proteins; C484384:Rbm3 protein, mouse; C482720:Rtn3 protein, mouse
keywords: RBM3; RTN3; cold shock; mRNA translation; neuroprotection; protein synthesis