Caractérisation du décalage du cadre de lecture de la protéine ataxine-3
Coding CAG repeat disorders have been associated with nine neurodegenerative disorders. Our group has previously shown that during the translation of mutant ataxine-3 (Atx3), the protein involved in Spinocerebellar Ataxia type 3 (SCA3), a ribosomal frameshift occurs and leads to the reading of a GCA frame rather than a CAG frame. This new reading frame causes the production of polyalanine in the polyglutamine peptide which increases its toxicity. Ribosomal frameshifts are known to occur in all organisms but little is known about this phenomenon in human. To study ribosomal frameshift along the ATXN3 transcript, we generated a transgenic Drosophila model in which we looked at the toxicity of the mRNA. Also, we developed a toeprinting assay to precisely evaluate where the change of reading frame occurs along the mRNA. Our results suggest that the toxicity observed in our Drosophila model results from the production of polyalanine and not from the presence of the mRNA per se. Moreover, the change in reading frame seems to occur at the 48th CAG codon and this pausing of the ribosome also occurs in other polyQ tracts. Because CAG repeat disorders share many characteristics, an alteration of the frameshift could alleviate symptoms of SCA3 patients as well as of many other diseases with coding CAG repeats.
Neurodegeneration Ribosomal frameshifting Ataxine-3 Ataxin-­3 Drosophila model