Abstract
Purpose :
Changes in protein synthesis are inherently linked to retinal ganglion cell (RGC) metabolism and survival. Yet, the specific mechanisms that modify mRNA translation during RGC degeneration are not clear. We have uncovered a pathway linking extracellular induction of the MAPK (mitogen activated protein kinase) ERK to alter translational control in injured RGCs. This signaling is mediated through the activities of MNKs (MAPK interacting serine/threonine kinases), to specifically alter the function of eIF4E (eukaryotic translation initiation factor 4E). eIF4E is a key component of cap-dependent mRNA translation, but exhibits preferences for translating specific subsets of mRNAs in different tissues and contexts. Using next-gen ribosomal profiling (riboseq), we tested whether MAPK-MNK-eIF4E pathway drives altered translation of specific cohorts of mRNAs to impact RGC survival.
Methods :
Pharmacologic and genetic tools were used to assess the histological and functional impact of MNK-eIF4E signaling in kainic acid (KA) and intraocular pressure-induced models of RGC degeneration. To determine differentially translated mRNAs, riboseq was performed in retinas of wild-type mice, or a strain containing an eIF4E single amino acid knock-in (KI) that inactivates MNK signaling. Rapid translational changes were assessed following KA injury. Ribosome-protected mRNAs were then purified and sequenced for identification of differentially translated transcripts, followed by informatic and pathways analyses.
Results :
In both injury models inhibition of eIF4E signaling was demonstrated to significantly protect RGC survival and function. Ribosomal profiling uncovered injury-related transcripts that were significantly differentially translated in WT retinas after KA treatment, compared to unchallenged controls (p<0.01). Remarkably, of these only 11 of these transcripts were sensitive and specific to ERK-MNK signaling (p<0.01). Informatic analyses identified several pathways involved in neuronal activity.
Conclusions :
This work uncovered rapid translational changes in the retina after degenerative injury that are eIF4E-dependent for a subset of genes. This novel area can be further studied to better understand neurodegeneration, and presents an opportunity to selectively fine-tune translation to promote RGC survival and function.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.