Journal Article

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

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

2018

Overview

The major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a C9orf72 G 4 C 2 repeat expansion 1 , 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. ALS/FTD-related C9orf72 dipeptide-repeat proteins inhibit protein translation and impair stress granule dynamics, and they cause motor and cognitive deficits in mice.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/378 / 631/378/1689 / 631/378/1934 / 692/699/375 / Age / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - metabolism / Animals / Atrophy / Behavior, Animal / Biocompatibility / Biomedical and Life Sciences / Biomedicine / Brain / C9orf72 Protein - metabolism / Cancer Research / Care and treatment / 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 / Genes / Genetic aspects / Granular materials / HEK293 Cells / Homeostasis / Humans / Infectious Diseases / Initiation factor eIF-3 / Laboratory rats / Letter / Medical schools / Metabolic Diseases / Mice / Mice, Inbred C57BL / Molecular Medicine / Neurodegeneration / Neurophysiology / Neurosciences / Pathogenesis / Protein Biosynthesis - drug effects / Proteins / Psychological aspects / Ribonucleic acid / Ribosomal Proteins - metabolism / Ribosomal subunits / RNA / Stress, Physiological - drug effects / Stresses / Toxicity / Translation / Translation (Genetics)