CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation

Machado-Joseph disease (MJD) is one of several disorders caused by the expa nsion of a coding CAG repeat (exp-CAG), The presence of intranuclear inclus ions (INIs) in patients and cellular models of exp-CAG-associated diseases has lead to a nuclear toxicity model. Similar INIs are found in oculopharyn geal muscular dystrophy, which is caused by a short expansion of an alanine -encoding GCG repeat. Here we propose that transcriptional or translational frameshifts occurring within expanded CAG tracts result in the production and accumulation of polyalanine-containing mutant proteins. We hypothesize that these alanine polymers deposit in cells forming INIs and may contribut e to nuclear toxicity. We show evidence that supports our hypothesis in lym phoblast cells from MJD patients, as well as in pontine neurons of MJD brai n and in in vitro cell culture models of the disease. We also provide evide nce that alanine polymers alone are harmful to cells and predict that a sim ilar pathogenic mechanism may occur in the other CAG repeat disorders.