Ribosomal frameshifting on MJD-1 transcripts with long CAG tracts.
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.
Toulouse
André
A
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.
Au-Yeung
Faith
F
Gaspar
Claudia
C
Roussel
Julie
J
Dion
Patrick
P
Rouleau
Guy A
GA
D000595:Amino Acid Sequence; D000841:Anisomycin / Q000494:pharmacology; D000067699:Ataxin-3; D002478:Cells, Cultured; D017931:DNA Primers; D005434:Flow Cytometry; D016368:Frameshift Mutation / Q000235:genetics; D018965:Frameshifting, Ribosomal / Q000187:drug effects / Q000235:genetics*; D049452:Green Fluorescent Proteins; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D010455:Peptides / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D012097:Repressor Proteins; D017422:Sequence Analysis, DNA; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
D017931:DNA Primers; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D000841:Anisomycin; C092341:ATXN3 protein, human; D000067699:Ataxin-3