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Nat Med. 2018 Aug;24(8):1136-1142. doi: 10.1038/s41591-018-0071-1. Epub 2018 Jun 25.

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

Author information

1
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
2
Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN, USA.
3
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
4
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
5
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
6
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. petrucelli.leonard@mayo.edu.
7
Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN, USA. petrucelli.leonard@mayo.edu.

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.

PMID:
29942091
DOI:
10.1038/s41591-018-0071-1

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