We have engineered a yeast system allowing to record Aß toxicity and used it to screen for highly toxic mutants. In parallel, we have developed specific skills to overproduce, purify and study in vitro these different Aß variants.

With the help of a biophysical group headed by S. Lecomte (CBMN, Bordeaux), we found that toxicity (measured in vivo in yeast) is related to the capacity to form (in vitro) specific fibrils organized in anti-parallel ß sheets. This group could also demonstrate that the more toxic mutants are also able to disrupt liposome integrity with the highest efficacity.

The yeast system allowed us also to screen different yeast KO libraries to identify the genes involved in cellular toxicity. We found that Aß needs to be secreted. ER retention of this peptide abrogates the deleterious effect. Finally, our screen led us to identify some genes related to membrane integrity surveillance as major actor of Aß toxicity.

In the frame of a collaboration with J. Winderickx (KUL, Leuven) who put in place a yeast model for Tau expression, we validated a yeast-based model displaying synergistic toxicity when human Aβ and Tau are co-expressed. Tau toxicity is concomitant with its hyperphophorylation and is specifically induced by Aß expression.

Altogether, these results make the budding yeast as a faithful model able to recapitulate the first steps of the “amyloid cascade” and should provide an interesting starting point for a fruitful discussion with the scientists who will take the time to meet me at this seminar !

Contact : remy.sadoul@ujf-grenoble.fr