RT Journal Article SR Electronic T1 TrkB signaling regulates the cold-shock protein RBM3-mediated neuroprotection JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202000884 DO 10.26508/lsa.202000884 VO 4 IS 4 A1 Diego Peretti A1 Heather L Smith A1 Nicholas Verity A1 Ibrahim Humoud A1 Lis de Weerd A1 Dean P Swinden A1 Joseph Hayes A1 Giovanna R Mallucci YR 2021 UL https://www.life-science-alliance.org/content/4/4/e202000884.abstract AB Increasing levels of the cold-shock protein, RNA-binding motif 3 (RBM3), either through cooling or by ectopic over-expression, prevents synapse and neuronal loss in mouse models of neurodegeneration. To exploit this process therapeutically requires an understanding of mechanisms controlling cold-induced RBM3 expression. Here, we show that cooling increases RBM3 through activation of TrkB via PLCĪ³1 and pCREB signaling. RBM3, in turn, has a hitherto unrecognized negative feedback on TrkB-induced ERK activation through induction of its specific phosphatase, DUSP6. Thus, RBM3 mediates structural plasticity through a distinct, non-canonical activation of TrkB signaling, which is abolished in RBM3-null neurons. Both genetic reduction and pharmacological antagonism of TrkB and its downstream mediators abrogate cooling-induced RBM3 induction and prevent structural plasticity, whereas TrkB inhibition similarly prevents RBM3 induction and the neuroprotective effects of cooling in prion-diseased mice. Conversely, TrkB agonism induces RBM3 without cooling, preventing synapse loss and neurodegeneration. TrkB signaling is, therefore, necessary for the induction of RBM3 and related neuroprotective effects and provides a target by which RBM3-mediated synapse-regenerative therapies in neurodegenerative disorders can be used therapeutically without the need for inducing hypothermia.