Department of Genetics Cell Biology and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):260-5. doi: 10.1073/pnas.1013343108. Epub 2010 Dec 20.
Trinucleotide expansions cause disease by both protein- and RNA-mediated mechanisms. Unexpectedly, we discovered that CAG expansion constructs express homopolymeric polyglutamine, polyalanine, and polyserine proteins in the absence of an ATG start codon. This repeat-associated non-ATG translation (RAN translation) occurs across long, hairpin-forming repeats in transfected cells or when expansion constructs are integrated into the genome in lentiviral-transduced cells and brains. Additionally, we show that RAN translation across human spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) CAG expansion transcripts results in the accumulation of SCA8 polyalanine and DM1 polyglutamine expansion proteins in previously established SCA8 and DM1 mouse models and human tissue. These results have implications for understanding fundamental mechanisms of gene expression. Moreover, these toxic, unexpected, homopolymeric proteins now should be considered in pathogenic models of microsatellite disorders.
三核苷酸扩展通过蛋白质和 RNA 介导的机制引起疾病。出乎意料的是，我们发现 CAG 扩展构建体在没有 ATG 起始密码子的情况下表达同源聚谷氨酰胺、聚丙氨酸和聚丝氨酸蛋白。这种重复相关的非 ATG 翻译（RAN 翻译）发生在转染细胞中的长发夹形成重复中，或者当扩展构建体整合到慢病毒转导细胞和大脑的基因组中时。此外，我们表明，跨越人类脊髓小脑共济失调 8 型（SCA8）和肌强直性营养不良 1 型（DM1）CAG 扩展转录本的 RAN 翻译导致 SCA8 聚丙氨酸和 DM1 聚谷氨酰胺扩展蛋白在先前建立的 SCA8 和 DM1 小鼠模型和人类组织中的积累。这些结果对于理解基因表达的基本机制具有重要意义。此外，这些有毒的、意想不到的、同源的蛋白质现在应该在微卫星疾病的致病模型中被考虑。
