Book of Abstracts: Albany 2005

category image Volume 22
No. 6
June 2005

Role of Translational Slippage of Long CAG Tracts in Neurological Disorders

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 spinocerebellar ataxia type 3 (SCA3/MJD) the expanded CAG tract is prone to -1 frameshifting that may lead to the production of polyalanine-containing proteins, in vivo and in vitro. To better document the occurrence of frameshifting and understand its mechanism and possible role in the pathogenesis of these diseases, we established a cellular model using a truncated MJD1 cDNA epitope-agged in all three reading frames. Here we show that this phenomenon results from ribosomal slippage to the -1 frame exclusively, and that the frequency of such events is dependent on the length of the CAG tract, with a threshold for frameshifting similar to that of pathological CAG length in patients. We also show that FS is dependent on the nature of the repetitive sequence, with FS frequencies drastically decreasing in the following repeat-type order: CAG>>CAACAG>CAA. Furthermore, in our system frameshifted proteins seem to enhance polyglutamine associated toxicity, possibly contributing to pathogenesis. Finally, we present evidence that anysomycin, a ribosome-interacting drug that reduces -1 frameshifting by inhibiting the accommodation of the tRNA to the ribosome, also reduces toxicity. These results contribute to the understanding of the disease process and suggest new therapeutic avenues for the expanded CAG tract disorders.

Guy Rouleau*
Andre Toulouse
Faith Au-Yeung
Claudia Gaspar
Julie Roussel
Patrick Dion

Department of Medicine and Research Center
Centre Hospitalier de l?Université de Montreal
Hopital Notre-Dame
Suite Y3616-2
1560 Sherbrooke Street East
Montreal, Quebec

*Phone: 514 890-8000 ext 24699
Fax: 514 412-7602
Email: guy.rouleau@umontreal.ca