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Published on: March 15, 2013
Expanded ATXN3 frameshifting events are toxic in Drosophila and mammalian neuron models
Shawn J Stochmanski1, Martine Therrien, Janet Laganière
1Center of Excellence in Neuroscience of the Université de Montréal (CENUM), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada.
Abstract:
Spinocerebellar ataxia type 3 is caused by the expansion of the coding CAG repeat in the ATXN3 gene. Interestingly, a -1 bp frameshift occurring within an (exp)CAG repeat would henceforth lead to translation from a GCA frame, generating polyalanine stretches instead of polyglutamine. Our results show that transgenic expression of (exp)CAG ATXN3 led to -1 frameshifting events, which have deleterious effects in Drosophila and mammalian neurons. Conversely, transgenic expression of polyglutamine-encoding (exp)CAA ATXN3 was not toxic. Furthermore, (exp)CAG ATXN3 mRNA does not contribute per se to the toxicity observed in our models. Our observations indicate that expanded polyglutamine tracts in Drosophila and mouse neurons are insufficient for the development of a phenotype. Hence, we propose that -1 ribosomal frameshifting contributes to the toxicity associated with (exp)CAG repeats.
Insights
Spinocerebellar ataxia type 3 (SCA3) toxicity may stem from -1 frameshifting events, not just expanded polyglutamine tracts. This frameshifting generates toxic polyalanine, implicating ribosomal frameshifting in SCA3 pathogenesis.
Area of Science:
- Neurogenetics
- Molecular Biology
- Cellular Biology
Background:
- Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by expanded CAG repeats in the ATXN3 gene, typically leading to polyglutamine expansions.
- The ATXN3 gene encodes the ataxin-3 protein, and expanded polyglutamine tracts are traditionally considered the primary cause of SCA3 toxicity.
Purpose of the Study:
- To investigate the role of -1 frameshifting events within expanded CAG repeats in the ATXN3 gene.
- To determine if polyalanine stretches, generated by frameshifting, contribute to SCA3 pathogenesis.
- To differentiate the toxicity of expanded polyglutamine tracts from that caused by frameshifting.
Main Methods:
- Transgenic expression of expanded CAG ATXN3 and expanded CAA ATXN3 in Drosophila and mammalian neuronal models.
- Analysis of frameshifting events within the expanded repeats.
- Assessment of toxicity and phenotypic consequences in neuronal cells.
Main Results:
- Transgenic expression of expanded CAG ATXN3 induced -1 frameshifting events, leading to the production of polyalanine stretches.
- These polyalanine stretches exhibited deleterious effects in both Drosophila and mammalian neurons.
- Transgenic expression of polyglutamine-encoding expanded CAA ATXN3 did not cause toxicity.
- The mRNA of expanded CAG ATXN3 alone did not account for the observed toxicity.
- Expanded polyglutamine tracts alone were insufficient to cause a phenotype in the studied models.
Conclusions:
- Expanded polyglutamine tracts in ATXN3 are not solely responsible for SCA3-related toxicity.
- -1 ribosomal frameshifting within expanded CAG repeats contributes significantly to SCA3 pathogenesis by generating toxic polyalanine stretches.
- Ribosomal frameshifting is a critical mechanism to consider in the molecular basis of spinocerebellar ataxia type 3.
