The Ubiquitin Proteasome System in neurodegeneration and cytoskeleton architecture

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 of 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, 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


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Our group is dedicated to deciphering the pathophysiology of GAN but also to developing a specific diagnostic test and the first therapeutic approaches for this fatale disease. We are studying the pathways of cell death and cytoskeleton dynamics in new neuronal models that are also used as readout tests to evaluate the efficacy of newly generated therapeutic vehicles. We are using multidisciplinary approaches encompassing human genetics, cell and molecular biology, biochemistry, in vitro and in vivo imaging and animal models.

 

 

Major publications

Colin E et al., Am J Hum Genet., 99(3):695-703 (2016)
Angebault C et al., Am J Hum Genet., 97(5):754-60 (2015)
Mahammad S et al.,  J Clin Invest., 123(5):1964-75, (2013)
Cleveland DW et al., Hum Mol Genet., 18(8):1384-94, (2009)
Bomont P et al., EMBO J., 24(22):3927-39, (2005)
Bomont P et al., Hum Mol Genet., 12(8):813-22, (2003)
Bomont P et al., Nat Genet., 26(3):370-4, (2000)

Collaborations

  • Jean-Pierre Julien (Université Laval, Quebec, Canada)
  • Robert D. Goldman (Université Northwestern, Chicago, USA)
  • Brenda A. Schulman (St. Jude Children’s Research Hospital, Memphis, USA)
  • François Rivier (CHRU Montpellier, France)
  • Serge Urbach (Protéomique fonctionnelle-IGF, Montpellier)

Fundings

Logo Inserm    Logo ATIP Avenir  
Logo LR       FRM    Logo AFM

Contact

Pascale Bomont