Journal Article

Non-ATG-initiated translation directed by microsatellite expansions

Zu, Tao, Low, Walter C, Markowski, Todd W, Stone, Matthew D, Margolis, Jamie, Schmechel, Stephen, Swanson, Maurice S, Gomes-Pereira, Mário, Moseley, Melinda, Ranum, Laura P.W, Huguet, Aline, Clark, H. Brent, Gibbens, Brian, Doty, Noelle S, Schoser, Benedikt, Bitterman, Peter B, Gourdon, Geneviève, Somia, Nikunj V, Forster, Colleen, Ingram, Melissa A.C, Nan, Zhenhong, Peterson, Mark

2011

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Amino Acid Sequence / animal models / Antibodies / ataxia (disorder) / Biological Sciences / Blotting, Northern / Brain / Cell Line / Cells / Cellular immunity / Cloning, Molecular / Codon, Initiator - genetics / DNA Primers - genetics / Dystrophy / Fluorescent Antibody Technique / Gene expression / Genetic mutation / Genetic Vectors / Genomics / Humans / Huntington disease / Immunoblotting / Immunohistochemistry / Immunoprecipitation / Lentivirus / Mass Spectrometry / microsatellite repeats / Microsatellites / Molecular Sequence Data / Mutagenesis / Myotonic dystrophy / Myotonic Dystrophy - genetics / Peptides - genetics / Peptides - metabolism / Protein Biosynthesis - genetics / Protein Biosynthesis - physiology / Proteins / Purkinje cells / Reverse Transcriptase Polymerase Chain Reaction / Ribonucleic acid / RNA / Rodents / Spinocerebellar Ataxias - genetics / Start codon / toxicity / translation (genetics) / Trinucleotide Repeat Expansion - genetics