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Human Molecular Genetics Advance Access published online on August 8, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi299
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received June 16, 2005
Revised August 1, 2005
Accepted August 1, 2005

Article

Ribosomal frameshifting on MJD transcripts with long CAG tracts

André Toulouse 1, Faith Au-Yeung 1, Claudia Gaspar 1, Julie Roussel 1, Patrick Dion 1, and Guy A. Rouleau 2*

1 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
2 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; Department of Medicine and Research Centre, Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame, suite Y3633-1, 1560 Sherbrooke Street East, Montreal, Qc, H2L 4M1, Canada

* To whom correspondence should be addressed.
Guy A. Rouleau, E-mail: Guy.Rouleau{at}umontreal.ca


  Abstract

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 in SCA3 that the expanded CAG tract in the MJD-1 transcript is prone to frameshifting that may lead to the production of polyalanine-containing proteins. To further document 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 avenue for these disorders.


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