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

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

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalNature Medicine
DOIs
StateAccepted/In press - Jun 25 2018

Fingerprint

Amyotrophic Lateral Sclerosis
Protein Biosynthesis
Dipeptides
Proteins
Brain
Ribosome Subunits
Peptide Initiation Factors
Memory Disorders
Ribosomes
Atrophy
Homeostasis
Mountings
RNA
Toxicity
Genes
Frontotemporal Dementia With Motor Neuron Disease
Data storage equipment
Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. / Zhang, Yongjie; Gendron, Tania D; Ebbert, Mark T.W.; O’Raw, Aliesha D.; Yue, Mei; Jansen-West, Karen; Zhang, Xu; Prudencio, Mercedes; Chew, Jeannie; Cook, Casey; Daughrity, Lillian M.; Tong, Jimei; Song, Yuping; Pickles, Sarah R.; Castanedes-Casey, Monica; Kurti, Aishe; Rademakers, Rosa V; Oskarsson, Bjorn; Dickson, Dennis W; Hu, Wengian; Gitler, Aaron D.; Fryer, John D.; Petrucelli, Leonard.

In: Nature Medicine, 25.06.2018, p. 1-7.

Research output: Contribution to journalArticle

Zhang, Yongjie ; Gendron, Tania D ; Ebbert, Mark T.W. ; O’Raw, Aliesha D. ; Yue, Mei ; Jansen-West, Karen ; Zhang, Xu ; Prudencio, Mercedes ; Chew, Jeannie ; Cook, Casey ; Daughrity, Lillian M. ; Tong, Jimei ; Song, Yuping ; Pickles, Sarah R. ; Castanedes-Casey, Monica ; Kurti, Aishe ; Rademakers, Rosa V ; Oskarsson, Bjorn ; Dickson, Dennis W ; Hu, Wengian ; Gitler, Aaron D. ; Fryer, John D. ; Petrucelli, Leonard. / Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. In: Nature Medicine. 2018 ; pp. 1-7.
@article{d407eb802a1b4a1d9f2875f2b6c76196,
title = "Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis",
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.",
author = "Yongjie Zhang and Gendron, {Tania D} and Ebbert, {Mark T.W.} and O’Raw, {Aliesha D.} and Mei Yue and Karen Jansen-West and Xu Zhang and Mercedes Prudencio and Jeannie Chew and Casey Cook and Daughrity, {Lillian M.} and Jimei Tong and Yuping Song and Pickles, {Sarah R.} and Monica Castanedes-Casey and Aishe Kurti and Rademakers, {Rosa V} and Bjorn Oskarsson and Dickson, {Dennis W} and Wengian Hu and Gitler, {Aaron D.} and Fryer, {John D.} and Leonard Petrucelli",
year = "2018",
month = "6",
day = "25",
doi = "10.1038/s41591-018-0071-1",
language = "English (US)",
pages = "1--7",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

AU - Zhang, Yongjie

AU - Gendron, Tania D

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

AU - Daughrity, Lillian M.

AU - Tong, Jimei

AU - Song, Yuping

AU - Pickles, Sarah R.

AU - Castanedes-Casey, Monica

AU - Kurti, Aishe

AU - Rademakers, Rosa V

AU - Oskarsson, Bjorn

AU - Dickson, Dennis W

AU - Hu, Wengian

AU - Gitler, Aaron D.

AU - Fryer, John D.

AU - Petrucelli, Leonard

PY - 2018/6/25

Y1 - 2018/6/25

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.

UR - http://www.scopus.com/inward/record.url?scp=85048952425&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048952425&partnerID=8YFLogxK

U2 - 10.1038/s41591-018-0071-1

DO - 10.1038/s41591-018-0071-1

M3 - Article

C2 - 29942091

AN - SCOPUS:85048952425

SP - 1

EP - 7

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

ER -