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RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration

Peretti, Diego; Bastide, Amandine; Radford, Helois; Verity, Nicholas; Molloy, Colin; Martin, Maria Guerra; Moreno, Julie A.; Steinert, Joern R.; Smith, Tim; Dinsdale, David; Willis, Anne E.; Mallucci, Giovanna R.


Diego Peretti

Amandine Bastide

Helois Radford

Nicholas Verity

Colin Molloy

Maria Guerra Martin

Julie A. Moreno

Tim Smith

David Dinsdale

Anne E. Willis

Giovanna R. Mallucci


In the healthy adult brain synapses are continuously remodelled through a process of elimination and formation known as structural plasticity1. Reduction in synapse number is a consistent early feature of neurodegenerative diseases2,3, suggesting deficient compensatory mechanisms. Although much is known about toxic processes leading to synaptic dysfunction and loss in these disorders2,3, 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 plasticity4,5. 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) mice7, 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.


Peretti, D., Bastide, A., Radford, H., Verity, N., Molloy, C., Martin, M. G., …Mallucci, G. R. (2015). RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration. Nature, 518(7538), 236-239.

Journal Article Type Article
Acceptance Date Dec 5, 2014
Online Publication Date Jan 14, 2015
Publication Date 2015-02
Deposit Date Jun 17, 2020
Journal Nature
Print ISSN 0028-0836
Electronic ISSN 1476-4687
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 518
Issue 7538
Pages 236-239
Public URL
Publisher URL
Additional Information Received: 25 September 2013; Accepted: 5 December 2014; First Online: 14 January 2015; : The authors declare no competing financial interests.