Non-ATG-initiated translation directed by microsatellite expansions

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

Research output: Contribution to journalArticle

461 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)260-265
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number1
DOIs
StatePublished - Jan 4 2011

Keywords

  • Bidirectional expression
  • Neurodegeneration
  • Translation initiation

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    Zu, T., Gibbens, B., Doty, N. S., Gomes-Pereira, M., Huguet, A., Stone, M. D., Margolis, J., Peterson, M., Markowski, T. W., Ingram, M. A. C., Nan, Z., Forster, C., Low, W. C., Schoser, B., Somia, N. V., Clark, H. B., Schmechel, S., Bitterman, P. B., Gourdon, G., ... Ranum, L. P. W. (2011). Non-ATG-initiated translation directed by microsatellite expansions. Proceedings of the National Academy of Sciences of the United States of America, 108(1), 260-265. https://doi.org/10.1073/pnas.1013343108