Human Molecular Genetics Advance Access originally published online on August 8, 2005
Human Molecular Genetics 2005 14(18):2649-2660; doi:10.1093/hmg/ddi299
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Ribosomal frameshifting on MJD-1 transcripts with long CAG tracts
Department of Medicine and Research Center, Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame, Suite Y3616–2, 1560 Sherbrooke Street East, Montreal, Quebec H2L 4M1, Canada
* To whom correspondence should be addressed. Tel: +1 5148908000 ext. 24753; Fax: +1 5144127602; Email: guy.rouleau{at}umontreal.ca
Received June 16, 2005; Revised August 1, 2005; Accepted August 1, 2005
The expanded CAG tract diseases are a heterogeneous group of late-onset neurodegenerative disorders characterized by the accumulation of insoluble protein material and premature neuronal cell death. Recent work has provided support for several mechanisms that may account for neurodegeneration, but no unifying mechanism has emerged. We have previously demonstrated that in SCA3, the expanded CAG tract in the MJD-1 transcript is prone to frameshifting, which may lead to the production of polyalanine-containing proteins. To further examine the occurrence of frameshifting and understand its mechanism and possible role in pathogenesis, a cellular model was established. We show that this phenomenon results from ribosomal slippage to the –1 frame exclusively, that ribosomal frameshifting depends on the presence of long CAG tracts and that polyalanine-frameshifted proteins may enhance polyglutamine-associated toxicity, possibly contributing to pathogenesis. Finally, we present evidence that anisomycin, a ribosome-interacting drug that reduces –1 frameshifting, also reduces toxicity, suggesting a new therapeutic opportunity for these disorders.
Present address: Department of Anatomy/Neuroscience, University College Cork, Cork, Ireland.
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