title: RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration.
abstract: In the healthy adult brain synapses are continuously remodelled through a process of elimination and formation known as structural plasticity. Reduction in synapse number is a consistent early feature of neurodegenerative diseases, suggesting deficient compensatory mechanisms. Although much is known about toxic processes leading to synaptic dysfunction and loss in these disorders, how synaptic regeneration is affected is unknown. In hibernating mammals, cooling induces loss of synaptic contacts, which are reformed on rewarming, a form of structural plasticity. We have found that similar changes occur in artificially cooled laboratory rodents. Cooling and hibernation also induce a number of cold-shock proteins in the brain, including the RNA binding protein, RBM3 (ref. 6). The relationship of such proteins to structural plasticity is unknown. Here we show that synapse regeneration is impaired in mouse models of neurodegenerative disease, in association with the failure to induce RBM3. In both prion-infected and 5XFAD (Alzheimer-type) mice, the capacity to regenerate synapses after cooling declined in parallel with the loss of induction of RBM3. Enhanced expression of RBM3 in the hippocampus prevented this deficit and restored the capacity for synapse reassembly after cooling. RBM3 overexpression, achieved either by boosting endogenous levels through hypothermia before the loss of the RBM3 response or by lentiviral delivery, resulted in sustained synaptic protection in 5XFAD mice and throughout the course of prion disease, preventing behavioural deficits and neuronal loss and significantly prolonging survival. In contrast, knockdown of RBM3 exacerbated synapse loss in both models and accelerated disease and prevented the neuroprotective effects of cooling. Thus, deficient synapse regeneration, mediated at least in part by failure of the RBM3 stress response, contributes to synapse loss throughout the course of neurodegenerative disease. The data support enhancing cold-shock pathways as potential protective therapies in neurodegenerative disorders.
authors.affiliation: Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Diego
authors.initials: D
authors.lastname: Peretti
authors.affiliation: Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Amandine
authors.initials: A
authors.lastname: Bastide
authors.affiliation: Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Helois
authors.initials: H
authors.lastname: Radford
authors.affiliation: Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Verity
authors.affiliation: Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Molloy
authors.affiliation: Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Maria Guerra
authors.initials: MG
authors.lastname: Martin
authors.affiliation: Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Moreno
authors.affiliation: Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Joern R
authors.initials: JR
authors.lastname: Steinert
authors.affiliation: Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Smith
authors.affiliation: Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: David
authors.initials: D
authors.lastname: Dinsdale
authors.affiliation: Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Willis
authors.affiliation: 1] Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK [2] Department of Clinical Neurosciences, Clifford Allbutt Building, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0AH, UK.
authors.forename: Giovanna R
authors.initials: GR
authors.lastname: Mallucci
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D057773:Cold Shock Proteins and Peptides / Q000378:metabolism; D003080:Cold Temperature; D058639:Cold-Shock Response / Q000502:physiology*; D004195:Disease Models, Animal; D006605:Hibernation / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology*; D009473:Neuronal Plasticity; D018696:Neuroprotective Agents; D011328:Prions / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D013569:Synapses / Q000378:metabolism*
chemical_list: D057773:Cold Shock Proteins and Peptides; D018696:Neuroprotective Agents; D011328:Prions; D016601:RNA-Binding Proteins; C484384:Rbm3 protein, mouse