Abstract
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 PLCγ1 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.
Highlights
In the healthy adult brain, synapses are continually lost and replaced through structural plasticity, a process critical for repair that underlies learning and memory (Kandel et al, 2014; Bailey et al, 2015)
We showed that failure to induce RNA-binding motif 3 (RBM3) expression underlies the impaired synapse regenerative capacity underlying the earliest stages of synapse loss in several mouse models of neurodegenerative disease (Peretti et al, 2015)
Using our established cooling-rewarming paradigm for induction of RBM3 and structural plasticity in wild-type mice (Peretti et al, 2015; Bastide et al, 2017), we show that RBM3 expression is induced through brain-derived neurotrophic factor (BDNF)-TrkB signaling involving activation of the PLCγ1-CREB branch on cooling leading to a non-canonical inhibition of p-ERK branch activation by RBM3 through a previously unknown feedback loop
Summary
In the healthy adult brain, synapses are continually lost and replaced through structural plasticity, a process critical for repair that underlies learning and memory (Kandel et al, 2014; Bailey et al, 2015). Failure of this process leads to synapse loss and, eventually, neuronal demise. Increasing neuronal RBM3 levels, induced either through cooling or by lentivirally-mediated overexpression, restores synapse number and is profoundly neuroprotective in prion-diseased and in Alzheimer’s mouse models, rescuing cognitive deficits, preventing neuronal loss, and markedly increasing survival (Peretti et al, 2015) RBM3’s neuroprotective effects appear to be mediated largely through its downstream effector, reticulon 3 protein, RTN3 (Bastide et al, 2017), the exact mechanism of synapse regeneration is unknown. RBM3 is known to increase global protein synthesis rates (Dresios et al, 2004), in dendrites (Smart et al, 2007) and to regulate neuronal polarity (Pilotte et al, 2018) and neurogenesis during development (Xia et al, 2018), which may contribute to its effects on structural plasticity
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