2.1 Mechanisms of cochlear endoplasmic reticulum stress

Endoplasmic reticulum (ER) is the key organelle for the synthesis of secreted and transmembrane proteins. Perturbations in ER lead to an accumulation of unfolded or misfolded proteins. As a consequence, the unfolded protein response (UPR) adapts ER capacity to demand. Under prolonged stress, UPR switches from a cell survival promoter to an apoptosis trigger. ER stress thus emerges as a potential cause of deafness.


2 1 illustration 01

Identification of altered pathways in auditory deficits animal models require complementary approaches, which include molecular to cellular biology together with 2D gel electrophoresis, mass spectrometry and bioinformatic analysis. Here, the ER in HeLa cells is localized by the calreticulin immunostaining (green). Nucleus is shown in blue.

 

 


2 1 illustration 02

Here, we identified different altered hub proteins in the Tmprss3Y260X mutant mice. Notably, 15 proteins belong to the homeostasis of the ER, i.e., disulfide isomerases, oxydoreductases and lectins. The overexpression of these markers indicates an adaptive response (the Unfolded Protein Response, UPR) to prevent the accumulation of unfolded protein induced by ER stress.



Major publications

Molina et al., Human Mol Genet, 22(7):1289-99, 2013
Fasquelle et al., JBC, 286(19):17383-97, 2010
Delprat et al., Dev Dyn, 236(9):2534-40, 2007
Delprat et al., JBC, 282(10):7450-6, 2005
Delprat et al., Human Mol Genet, 14: 401-410, 2005
Delprat et al., Mol Cell Biol, 25: 847-853, 2005

Collaborations

  • Franck Molina (Sysdiag, Montpellier)
  • Eric Chevet (Avenir Team, Bordeaux)
  • Michel Guipponi (University of Geneva, Switzerland)

Fundings

ANR 150 par 150   Maladies Rareslogo LR-3-petit

Contact

Benjamin Delprat