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.
|Number of pages||7|
|State||Published - Aug 1 2018|
Bibliographical noteFunding Information:
We are grateful to all patients who agreed to donate post-mortem tissue. This work was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke (R35NS097273 (L.P.); P01NS084974 (L.P., D.W.D., R.R. and B.O.); P01NS099114 (T.F.G. and L.P.); R01NS088689 (L.P.); R35NS097263(10) (A.D.G.)); the Mayo Clinic Foundation (L.P.); the Amyotrophic Lateral Sclerosis Association (T.F.G., L.P., Y.-J.Z. and M.P.), the Robert Packard Center for ALS Research at Johns Hopkins (A.D.G. and L.P.) and the Target ALS Foundation (T.F.G., A.D.G., L.P. and Y.-J.Z.). We would like to thank J. N. Stankowski, E. A. Perkerson, L. Rousseau and V. Phillips for technical support. This manuscript is dedicated to Dr Antimo D’Aniello.
© 2018, The Author(s).
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)