Mechanisms underlying the direct repression of FOXO by developmental factors and the induction of neuron survival deficiency – FOXODIRECT

The approach in this project relies on models and methods that allow to study specific mechanisms while allowing a global view of regulatory phenomenons to be obtained at the genomic level.

At this stage of project, results relate to the exploitation of materials and tools that underlie the project.

The expected outcome of the project is to best understand the regulation of cellular longevity in Huntington's disease, which may have therapeutic potential.

Papers have been submitted to conferences and journals.

Neuronal cell decline in neurodegenerative disease can be caused by inherited mutations and consists of neuron dysfunction followed by neuron demise. The ability of neurons to cope with the chronic stress induced by mutant protein expression may determine the course of their decline and demise, which may impact on disease progression. Although the pathophysiological importance of neuronal stress response was previously illustrated, very little is known about the mechanisms that may regulate neuronal cell homeostasis during the early phases of the pathogenic process in neurodegenerative disease. In particular, how neuron differentiation and cell survival factors may closely interact to regulate neuron survival in neurodegenerative disease remains poorly understood. We found that a receptor important for neurogenesis is increased in several models of Huntington’s disease (HD), which may occur during the early phases of the disease process. The increase of this receptor directly represses FOXO transcription factors, a protein family that is central to cell survival/longevity and that is important to neuron homeostasis and neuroprotection. We postulate that neurons are unable to develop a fully-efficient FOXO-mediated survival response during the very early phases of the pathogenic process in HD, which may have strong therapeutic implications for the design of successful disease-modifying strategies. On these grounds, our project is to use several models of HD to further investigate how FOXO is repressed by developmental signaling in mutant polyglutamine neurons and how this may alter neuron survival genes downstream to FOXO. Our project will also investigate how the repression of FOXO may be inhibited to restore a full neuron survival ability in HD. This project is expected to advance our understanding of the regulation of neuron survival in HD and to foster the development of successful disease-modifying strategies for HD and perhaps other neurodegenerative diseases.