Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

Yong Jie Zhang, Tania F. Gendron, Mark T.W. Ebbert, Aliesha D. O’Raw, Mei Yue, Karen Jansen-West, Xu Zhang, Mercedes Prudencio, Jeannie Chew, Casey N. Cook, Lillian M. Daughrity, Jimei Tong, Yuping Song, Sarah R. Pickles, Monica Castanedes-Casey, Aishe Kurti, Rosa Rademakers, Bjorn E Oskarsson, Dennis W. Dickson, Wenqian HuAaron D. Gitler, John D. Fryer, Leonard Petrucelli

Research output: Contribution to journalLetter

58 Scopus citations

Abstract

The major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a C9orf72 G4C2 repeat expansion1,2. Proposed mechanisms by which the expansion causes c9FTD/ALS include toxicity from repeat-containing RNA and from dipeptide repeat proteins translated from these transcripts. To investigate the contribution of poly(GR) dipeptide repeat proteins to c9FTD/ALS pathogenesis in a mammalian in vivo model, we generated mice that expressed GFP–(GR)100 in the brain. GFP–(GR)100 mice developed age-dependent neurodegeneration, brain atrophy, and motor and memory deficits through the accumulation of diffuse, cytoplasmic poly(GR). Poly(GR) co-localized with ribosomal subunits and the translation initiation factor eIF3η in GFP–(GR)100 mice and, of importance, in c9FTD/ALS patients. Combined with the differential expression of ribosome-associated genes in GFP–(GR)100 mice, these findings demonstrate poly(GR)-mediated ribosomal distress. Indeed, poly(GR) inhibited canonical and non-canonical protein translation in HEK293T cells, and also induced the formation of stress granules and delayed their disassembly. These data suggest that poly(GR) contributes to c9FTD/ALS by impairing protein translation and stress granule dynamics, consequently causing chronic cellular stress and preventing cells from mounting an effective stress response. Decreasing poly(GR) and/or interrupting interactions between poly(GR) and ribosomal and stress granule-associated proteins may thus represent potential therapeutic strategies to restore homeostasis.

Original languageEnglish (US)
Pages (from-to)1136-1142
Number of pages7
JournalNature Medicine
Volume24
Issue number8
DOIs
StatePublished - Aug 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Zhang, Y. J., Gendron, T. F., Ebbert, M. T. W., O’Raw, A. D., Yue, M., Jansen-West, K., Zhang, X., Prudencio, M., Chew, J., Cook, C. N., Daughrity, L. M., Tong, J., Song, Y., Pickles, S. R., Castanedes-Casey, M., Kurti, A., Rademakers, R., Oskarsson, B. E., Dickson, D. W., ... Petrucelli, L. (2018). Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Nature Medicine, 24(8), 1136-1142. https://doi.org/10.1038/s41591-018-0071-1