Center 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.
Hum Mol Genet. 2012 May 15;21(10):2211-8. doi: 10.1093/hmg/dds036. Epub 2012 Feb 14.
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.
脊髓小脑共济失调 3 型是由 ATXN3 基因中编码 CAG 重复扩展引起的。有趣的是，(exp)CAG 重复内发生的-1bp 移码会导致从 GCA 框架翻译，产生多聚丙氨酸而不是多聚谷氨酰胺。我们的结果表明，(exp)CAG ATXN3 的转基因表达导致-1 移码事件，这对果蝇和哺乳动物神经元有有害影响。相反，编码多聚谷氨酰胺的(exp)CAA ATXN3 的转基因表达没有毒性。此外，(exp)CAG ATXN3 mRNA 本身不会导致我们模型中观察到的毒性。我们的观察表明，果蝇和小鼠神经元中扩展的多聚谷氨酰胺片段不足以形成表型。因此，我们提出-1 核糖体移码有助于与(exp)CAG 重复相关的毒性。
