RHIRE

In our modern societies, the rate of nervous system disorders is continuously growing and represents a major public health issue. Indeed, our lifestyle and the substantial ageing of the population participate to the massive development of neurodegenerative diseases and traumatic injuries. As of today, no treatment is available to heal these patients. Neuronal death or circuit disruption, in the central nervous system (CNS), induces permanent loss of sensory, motor and cognitive functions as central nervous system neurons do not regenerate. If we long thought that the CNS axons environment was determinant in the CNS failure of axonal regrowth, recent studies demonstrated that these neurons intrinsically lack the cellular programs to promote active regeneration. During the course of development and upon injury, molecular pathways regulating growth in neurons are shut down. Numerous studies addressed in detail mechanisms of gene transcription regulation, characterization of transcription factors, regulation at the epigenetic level and chromatin availability. These experiments revealed interesting targets, capable of stimulating axonal regeneration from few micrometres to several millimetre, particularly when used synergistically. But they ultimately failed to expose all the programs necessary to stimulate sufficient axonal growth in order to rebuild functional circuits after injury. Indeed, more than 70% of CNS neurons are still not responsive to current pro-regenerative molecules which restrains functional circuit formation. Thus, there is an urge to identify molecular candidates to set up novel therapeutic strategies for neuroprotection and regeneration of the injured mature CNS. It is now extensively described that mRNA and protein content do not correlate and cells rely on translational control to regulate the expression of key proteins. Our preliminary data focused on protein changes upon axon injury raised two intriguing and completely novel concepts: i) wild type Huntingtin (wt-HTT) protein plays a crucial role in CNS regeneration and ii) wt-HTT is a new translation regulator. Based on these observations, we hypothesize that wt-HTT is essential in CNS adult regeneration and controls the specific translation of key mRNA involved in axonal growth. The objective of this project is to show that HTT controls the specific translation of a subset of mRNA involved in neuroprotection and/or regeneration by interacting with the ribosome and the translational complex and targeting HTT and/or its mRNA targets is key to promote CNS neuroprotection and regeneration. To address these exciting and yet unexplored questions, we will use a combination of state-of-the-art biochemical and in vivo techniques, such as in vivo ribosome immunoprecipitation and translating ribosome affinity purification (TRAP) assays, proteomics analysis, molecular biology and mouse models of CNS injury. This project will answer the critical questions in General cellular biology as we will characterize an unexpected and new function for HTT as a translational regulator. In Neurobiology field, our results will uncover the role of HTT as a new major master regulator of axon regrowth and neuronal survival. We hope to move these candidates to pre-clinical stage in order to evaluate their potential to develop drugs and treatment for CNS injuries.