RTN3 Is a Novel Cold-Induced Protein and Mediates Neuroprotective Effects of RBM3

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.

Cold‐inducible protein RBM3 mediates hypothermic neuroprotection against neurotoxin rotenone via inhibition on MAPK signalling

“…However, mild hypothermia is an aggressive clinical therapy, bearing side‐effects such as shivering, slurred speech or mumbling, slow and shallow breathing, low energy and weak pulse . This inspired the search for molecular targets with fewer side‐effects to replace therapeutic cooling and led to the discovery of RBM3 as a crucial mediator of hypothermia‐related neuroprotection …”

“…There is growing evidence indicating that RBM3 is a crucial factor mediating hypothermia‐induced neuroprotective effects. In primary neurons and cortical organotypic slice cultures, mild hypothermia markedly increased RBM3 expression and rescued neuronal cells from forced apoptosis . In Alzheimer‐type and prion‐infected mouse models, RBM3 was identified as a crucial mediator of hypothermia‐induced neuroprotection, revealing that RBM3 induction/overexpression may provide protection not only in cases of acute brain injury but also in neurodegenerative diseases.…”

“…In primary neurons and cortical organotypic slice cultures, mild hypothermia markedly increased RBM3 expression and rescued neuronal cells from forced apoptosis. [17][18][19] In Alzheimer-type and prion-infected mouse models, RBM3 was identified as a crucial mediator of hypothermia-induced neuroprotection, 13 revealing that RBM3 induction/overexpression may provide protection not only in cases of acute brain injury but also in neurodegenerative diseases. We previously showed that the overexpression of RBM3 protects dopaminergic neuroblastoma cells SH-SY5Y from the apoptosis induced by nitric oxide (NO), ultra-violet (UV) irradiation and an overdose of retinoic acid (RA), whereas RBM3 knockdown revokes the neuroprotective effects of mild hypothermia in SH-SY5Y cells.…”

Neuroprotection via RNA-binding protein RBM3 expression is regulated by hypothermia but not by hypoxia in human SK-N-SH neurons

“…It has been demonstrated that RBM3 is able to mitigate cell death due to neurodegenerative diseases 25,41. Interestingly, in that context, a recent study identified RTN3, a protein that is involved in synapse function, as a target of RBM3 42. Taken together, further research is needed to address the possible targets and molecular functions of RBM3.…”

Determining Ribosome Translational Status by Ribo-ELISA

“…A convenient alternative is the freeze-thawing method which entails successive freezing (−80 °C) of 2 ml layered sucrose solutions starting from the highest sucrose concentration (50%, 40%, 30%, 20%, 10% w/v sucrose solutions) (Bastide et al, 2017). …”