Translational slippage and polyalanine toxicity in a cellular model for expanded CAG repeat disorders

The polyglutamine diseases are caused by an expansion of a CAG repeat sequence. This group of late-onset neurodegenerative disorders is characterised by neuronal cell death and the accumulation of polyglutamine-containing proteins. Several molecular mechanisms have been proposed that may explain disease pathogenesis.In this study, we propose a new pathogenic mechanism for these neurodegenerative diseases. We have demonstrated that expanded CAG stretches are prone to frameshifting to the -1 alanine-encoding GCA frame, and we propose that this phenomenon is due to ribosomal slippage during translation. This slippage depends on the presence of long CAG tracts, and generates polyalanine-containing proteins. We showed that polyalanines increase cell toxicity. Finally, we tested the effects of a ribosome-interacting drug and its ability to reduce or inhibit -1 translational frameshift and hence reduce cell toxicity. This drug introduces an avenue of potential treatment for these disorders