The Ubiquitin Proteasome System (UPS) is impaired in many neurodegenerative disorders and its role in neurodegeneration is the focus of intense scrutiny. However, solving its implication 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 models for this aim.
The identification of gigaxonin by our group, 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 model as a direct way to study the role of the UPS in neurodegeneration.
Extremely severe, GAN induces a wide range of deficits in the central and peripheral system, targeting the balance, the speech, the intellect, the vision, the motricity and the deep and superficial sensitivity. The broad degeneration of the nervous system together with the generalized disorganization of Intermediate Filaments in patients, point to a key role for gigaxonin in sustaining both neuronal survival and cytoskeleton architecture.
Combining fundamental research to translational development, our group is dedicated to (the) deciphering the pathophysiology of GAN but also to developing specific diagnostic tests and novel therapeutic approaches for this fatale disease. We are studying the pathways of cell death and cytoskeleton dynamics in vitro, in patient derived cells, in mouse derived neurons but also in vivo, by creating new mouse and zebrafish models for the disease. Together with clinicians and patients, we are also developing diagnostic tests to provide a differential diagnosis of GAN, and to generate robust readout tests to evaluate the efficacy of newly generated therapeutic vehicles. We are using a multidisciplinary approach encompassing human genetics, cell and molecular biology, biochemistry, in vitro and in vivo imaging, and behavioral analysis of animal models.
Colin E et al., Am J Hum Genet. 2016
Bomont P. Methods Enzymol. 2016
Angebault C et al. Am J Hum Genet. 2015
Boizot A et al. Acta Neuropathol Commun. 2014
Mahammad S et al. J Clin Invest. 2013
Ganay T et al. Mol Neurodegener. 2011
Cleveland D.W et al. Hum Mol Genet. 2009
Bomont P et al. EMBO J. 2005
Bomont P et al. Hum Mol Genet. 2003
Bomont P et al. Nat Genet. 2000
- Dominique Bonneau (University Hospital, Angers, France)
- Joel Eyer (MINT, Angers, France)
- Robert D Goldman (Northwestern University, Chicago, USA)
- Jean Pierre Julien (Laval University, Quebec, Canada)
- Guy Lenaers (University of Angers, France)
- Brenda A Schulman (St. Jude Children’s Research Hospital, Memphis, USA)
- Eise Sohara (Tokyo University, Japan)