Pascale BomontInstitut des neurosciences de Montpellier - Inserm / Université de Montpellier
Mes recherches
Starting with a PhD in Human Genetics in the laboratory of M. Koenig (IGBMC, Strasbourg), I delineated the genetic locus of several inherited diseases and developed bioinformatics methodologies to spot new genes among the colossal mass of sequences released by the ongoing Human Genome sequencing project. In 2000, I identified the gene mutated in a rare neurodegenerative disease called Giant Axonal Neuropathy (GAN), and pursued the study of this pathology during the last 19 years. My motivation finds its roots in the nature of the devastating symptoms in patients: degeneration of both peripheral and central nervous system and wide aggregation of the cytoskeletal Intermediate Filament (IF) throughout the body. Therefore, I crossed disciplines to apprehend the GAN disease in the most integrated manner. In 2003, I joined the laboratory of DW. Cleveland (LICR, San Diego, USA) in Cell Biology to study cytoskeleton dynamics, and was subsequently recruited at INSERM in 2007, in the laboratory of A. Represa (INMED, Marseille) to embrace Neuroscience and study neurodegeneration in mouse. With the support of AFM-Telethon, I was able to run my research program independently, and I obtained the ATIP-Avenir prize in 2011 to create my own research group at INM in Montpellier.
Studying a rare disease proved to be impactful for a broader fundamental knowledge and patient benefit. Indeed, we have demonstrated that the defective protein in GAN, the Gigaxonin-E3 ligase controls several fundamental biological processes: degradation of the cytoskeletal IF family, initiation of the autophagy pathway and induction of Shh signalling to generate motility. Moreover, development of novel methodologies and new animal models allowed us to develop diagnostic tools and identify candidate hits for therapeutic purpose, therefore opening opportunities to translate our research to patients.
In concluding, the ATIP-Avenir program represents a unique instrument in France to create the environment to deploy a scientific thematic. In my case, it constituted, together with patient’s driven associations (AFM-Telethon, FRM, FMR) and regional funding a critical template for my research program.
Mon projet ATIP-Avenir
Gigaxonin E3 ligase in neurodegeneration and cytoskeleton architecture:
pathological mechanisms and therapeutic approaches
Impaired in many common neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases, the Ubiquitin Proteasome System (UPS) has become a leading field over the past decade, and its role in neurodegeneration is the focus of intensive scrutiny. However, solving the implication of the UPS in neuronal death represents a considerable challenge and systems in which neurodegeneration is directly caused by mutations in component(s) of the UPS are very valuable. Our identification of gigaxonin, the substrate adaptor of a Cul3-E3 ubiquitin ligase, as the defective protein in the fatale neurodegenerative disorder Giant Axonal Neuropathy (GAN), prompted us to choose this pathology as a model to study the role of the UPS in neurodegeneration. Meaningfully, the broad degeneration of the entire nervous system, together with the wide aggregation of the cytoskeletal Intermediate Filament network in GAN support fundamental roles of Gigaxonin in sustaining general processes of neuron maintenance and cytoskeleton organization. With the rare disease GAN, this program aims to unravel these key biological functions, that will shed light onto the roles of the UPS in neurodegeneration, and to develop targeted therapies that can have an impact on other common neurodegenerative diseases.