Abstract
SummaryCooling 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.
Highlights
Therapeutic hypothermia is a powerful neuroprotectant, acting through multiple mechanisms, the underlying pathways are not fully understood [1, 2]
To examine the relationship between cold stress, RBM3 induction, and the modulation of mRNA translation for the synthesis of putative neuroprotective proteins, we investigated the post-transcriptional response to hypothermia in vitro and validated the data in vivo in a mouse model of neurodegeneration, in which we know cooling is protective, mediated by RBM3
In order to examine the genome-wide changes accompanying cooling, we incubated HEK293 cells at 32C for 24 hr. This resulted in reduction in protein synthesis (Figure 1A) and phosphorylation of the translation initiation and elongation factors eIF2a and eEF2 (Figure 1B; in agreement with previous studies [12])
Summary
Therapeutic hypothermia is a powerful neuroprotectant, acting through multiple mechanisms, the underlying pathways are not fully understood [1, 2]. We recently showed that the cold shock RNA-binding protein, RBM3, plays a critical role in mediating synaptic repair processes essential for neuroprotection in mouse models of neurodegenerative disease [3]. The inability to induce RBM3 expression in early disease results in defective structural synaptic plasticity and reduced regenerative capacity, leading to synapse loss and eventually neuronal loss. Inducing endogenous RBM3 expression in vivo through cooling, or by lentiviral-mediated overexpression, prevented synapse loss in prion and Alzheimer-type mice, rescued memory deficits, protected against neurodegeneration, and significantly prolonged survival [3]. How RBM3 mediates these effects is unknown, it is likely to be related to its RNA chaperone function, as it facilitates selective mRNA translation following a number of cellular stresses, including cooling [4,5,6]. RBM3 is implicated in protection against cell death [7, 8] and increases local protein synthesis at dendrites [9]
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