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

• Published in: Nature medicine Vol. 24; no. 8; pp. 1136 - 1142
• Main Authors: Zhang, Yong-Jie, Gendron, Tania F, Ebbert, Mark T W, O'Raw, Aliesha D, Yue, Mei, Jansen-West, Karen, Zhang, Xu, Prudencio, Mercedes, Chew, Jeannie, Cook, Casey N, Daughrity, Lillian M, Tong, Jimei, Song, Yuping, Pickles, Sarah R, Castanedes-Casey, Monica, Kurti, Aishe, Rademakers, Rosa, Oskarsson, Bjorn, Dickson, Dennis W, Hu, Wenqian, Gitler, Aaron D, Fryer, John D, Petrucelli, Leonard
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.08.2018
• Subjects: Age; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Animals; Atrophy; Behavior, Animal; Biocompatibility; Brain; C9orf72 Protein - metabolism; Cluster Analysis; Cytoplasmic Granules - drug effects; Cytoplasmic Granules - metabolism; Dementia; Dementia disorders; Dipeptides - pharmacology; Dismantling; Frontotemporal dementia; Frontotemporal Dementia - metabolism; Gene expression; Gene Expression Profiling; Granular materials; HEK293 Cells; Homeostasis; Humans; Initiation factor eIF-3; Mice; Mice, Inbred C57BL; Neurodegeneration; Pathogenesis; Protein Biosynthesis - drug effects; Proteins; Ribonucleic acid; Ribosomal Proteins - metabolism; Ribosomal subunits; RNA; Stress, Physiological - drug effects; Stresses; Toxicity; Translation
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-018-0071-1

The major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a C9orf72 G C repeat expansion . 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) in the brain. GFP-(GR) 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) mice and, of importance, in c9FTD/ALS patients. Combined with the differential expression of ribosome-associated genes in GFP-(GR) 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.