RAN Translation at C9orf72-Associated Repeat Expansions is Selectively Enhanced by the Integrated Stress Response

Authors

Katelyn M. Green, University of Michigan - Ann Arbor
M. Rebecca Glineburg, Chapman UniversityFollow
Michael G. Kearse, University of Michigan - Ann Arbor
Brittany N. Flores, University of Michigan - Ann Arbor
Alexander E. Linsalata, University of Michigan - Ann Arbor
Stephen J. Fedak, University of Michigan - Ann Arbor
Aaron C. Goldstrohm, University of Minnesota
Sami J. Barmada, University of Michigan - Ann Arbor
Peter K. Todd, University of Michigan - Ann Arbor

Document Type

Article

Publication Date

12-8-2017

Abstract

Repeat-associated non-AUG (RAN) translation allows for unconventional initiation at disease-causing repeat expansions. As RAN translation contributes to pathogenesis in multiple neurodegenerative disorders, determining its mechanistic underpinnings may inform therapeutic development. Here we analyze RAN translation at G₄C₂ repeat expansions that cause C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9RAN) and at CGG repeats that cause fragile X-associated tremor/ataxia syndrome. We find that C9RAN translation initiates through a cap- and eIF4A-dependent mechanism that utilizes a CUG start codon. C9RAN and CGG RAN are both selectively enhanced by integrated stress response (ISR) activation. ISR-enhanced RAN translation requires an eIF2α phosphorylation-dependent alteration in start codon fidelity. In parallel, both CGG and G₄C₂ repeats trigger phosphorylated-eIF2α-dependent stress granule formation and global translational suppression. These findings support a model whereby repeat expansions elicit cellular stress conditions that favor RAN translation of toxic proteins, creating a potential feed-forward loop that contributes to neurodegeneration.

Comments

This article was originally published in Nature Communications, volume 8, issue 1, in 2017. https://doi.org/10.1038/s41467-017-02200-0

Recommended Citation

Katelyn M. Green, M. Rebecca Glineburg, Michael G. Kearse, Brittany N. Flores, Alexander E. Linsalata, Stephen J. Fedak, Aaron C. Goldstrohm, Sami J. Barmada, and Peter K. Todd, “RAN translation at C9orf72- associated repeat expansions is selectively enhanced by the integrated stress response,” Nature Communications, 2017 Dec 8;8(1):2005. https://doi.org/10.1038/s41467-017-02200-0

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.