Assessing eIF4E-S209 Signaling and Translationally Regulated Mechanisms in Neurodegeneration

Neurodegeneration is a leading cause of morbidity and mortality. The causes of neurodegeneration are not well understood, but injury models have implicated mitogen activated protein kinase (MAPK) signaling cascades. The MAPKs extracellular signal-regulated kinase (ERK) and p38 can play an important role in translational control through the mRNA cap binding protein, eukaryotic translation initiation factor 4E (eIF4E). Downstream of stimuli, ERK or p38 can phosphorylate the MAPK interacting serine/threonine kinases (MNKs) 1 and 2. MNK1 or 2 then phosphorylate eIF4E, at a specific residue; serine 209 (S209). Phosphorylation of eIF4E-S209 by the MNKs can alter the subsets of mRNAs translated in response to stimuli that activate MAPKs. Differential translation induced by eIF4E-S209 phosphorylation is implicated in neurological disorders, but not yet in neurodegeneration despite strong links to MAPK activation. Therefore, I hypothesized that MAPK-mediated injury activates eIF4E-S209 dependent translation to promote neurodegeneration. Using a combination of small molecule inhibitors and genetic approaches, I verified activity of the MAPK-MNK-eIF4E signaling axis in vitro and in vivo in glutamatergic models of neurodegeneration. ERK, but not p38, was identified as the specific MAPK activated downstream of glutamate injury. Both pharmacologic and genetic inhibition of eIF4E-S209 activation protected viability of neuronal cells in vitro, and retinal neurons in vivo against ERK-mediated injury. Ribosome profiling was then used to capture and identify differentially translated mRNAs after neurodegenerative injury in vivo; of which a subset were eIF4E-S209 sensitive. Also identified were eIF4E-independent translations during injury, as well as eIF4E-S209 sensitive translations without injury. To my knowledge, this is the first study to implicate eIF4E-S209 signaling in ERK-mediated neurodegenerative injury. Understanding the ERK-MNK-eIF4E signaling axis, as well as translationally regulated mechanisms that contribute to neurodegeneration is a novel area that can potentially highlight new therapeutic targets.

Department dc:contributor.department

Laboratory Medicine and Pathobiology

Year dc:date.issued

2023

Author dc:creator

• Tuccitto, Maria Alessandra

Advisor dc:contributor.advisor

• Sivak, Jeremy M

• eIF4E
• Neurodegeneration
• Neuroprotection
• Retina
• Translation
• Vision

Handle dc:identifier.uri

http://hdl.handle.net/1807/138917

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/138917