Expanded ATXN3 frameshifting events are toxic in Drosophila and mammalian neuron models

摘要

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 _expCAG repeat would henceforth lead to translation from a GCA frame, generating polyalanine stretches instead of polyglutamine. Our results show that transgenic expression of _expCAG ATXN3 led to −1 frameshifting events, which have deleterious effects in Drosophila and mammalian neurons. Conversely, transgenic expression of polyglutamine-encoding _expCAA ATXN3 was not toxic. Furthermore, _expCAG 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 _expCAG repeats.