TY - JOUR
T1 - Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis
AU - Zhang, Yong Jie
AU - Gendron, Tania F.
AU - Ebbert, Mark T.W.
AU - O’Raw, Aliesha D.
AU - Yue, Mei
AU - Jansen-West, Karen
AU - Zhang, Xu
AU - Prudencio, Mercedes
AU - Chew, Jeannie
AU - Cook, Casey N.
AU - Daughrity, Lillian M.
AU - Tong, Jimei
AU - Song, Yuping
AU - Pickles, Sarah R.
AU - Castanedes-Casey, Monica
AU - Kurti, Aishe
AU - Rademakers, Rosa
AU - Oskarsson, Bjorn
AU - Dickson, Dennis W.
AU - Hu, Wenqian
AU - Gitler, Aaron D.
AU - Fryer, John D.
AU - Petrucelli, Leonard
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/8/1
Y1 - 2018/8/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41591-018-0071-1
DO - 10.1038/s41591-018-0071-1
M3 - Article
C2 - 29942091
AN - SCOPUS:85048952425
SN - 1078-8956
VL - 24
SP - 1136
EP - 1142
JO - Nature Medicine
JF - Nature Medicine
IS - 8
ER -