Specialized translational Complexes to Control Translation during Regeneration – SPECCTRE

Central Nervous System (CNS) neurons are not able to regenerate their axons after injury. This discrepancy is due to a dual mechanism: first axonal growth capability decreases during development and second, the lesion itself diminishes regenerative capabilities and induces neuronal death. Numerous studies have aimed to uncover axon regeneration and neuroprotective mechanisms by analyzing neuronal mRNA content during CNS development and injury. Even if those experiments revealed interesting targets promoting to some extent axonal regeneration, they ultimately failed to expose all the programs necessary to stimulate sufficient axonal growth in order to rebuild functional circuits after injury. Indeed, it is now extensively described that mRNA and protein content do not correlate in cells and cells rely on translational control to regulate the expression of key proteins. Indeed, several studies highlight that translational regulation is as important as transcriptional regulation. In addition, recent studies shows that the ribosome and more broadly the translational complex is actively involved in translation regulation by modulating its composition to match cellular specific needs. This study pioneered the emerging concept of “specialized ribosomes”. Interestingly, my recent results demonstrate that injury targets translation and specific components of the translational complex to control mRNA translation, growth and neuroprotective programs. Different studies during neuronal development also reach the same conclusions. Based on these observations, I propose an innovative and original approach to overcome CNS regeneration failure by focusing on the role of specialized translational machinery and translation regulation. The objective of my project is to address the two following working hypothesis in the model of the mouse Retina Ganglia Cells neurons during development, in adult and after optic nerve injury:
- The Translational complex will adapt its composition during development and injury to directly regulate expression at the translational level of key mRNA involved in growth and survival.
- Targeting those modifications and/or mRNAs will induce neuroprotection and/or regeneration in CNS after injury
My project will shed light on a paradigm shift: from a passive housekeeping translation complex to a direct translational regulator. My results will define the precise role of the translation complex during neuronal life and characterize which programs are controls at the translational level. Finally, my finding will lead to the development of new-targeted therapeutic strategies not only in case of CNS injuries but also for other neurodegenerative diseases.