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

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

doi:10.1038/s41591-018-0071-1

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

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

Research output: Contribution to journal › Article › peer-review

166 Scopus citations

Abstract

The major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a C9orf72 G₄C₂ 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.

Original language	English
Pages (from-to)	1136-1142
Number of pages	7
Journal	Nature Medicine
Volume	24
Issue number	8
DOIs	https://doi.org/10.1038/s41591-018-0071-1
State	Published - Aug 1 2018

Bibliographical note

Funding 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.

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (all)

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10.1038/s41591-018-0071-1

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Zhang, Y. J., Gendron, T. F., Ebbert, M. T. W., O’Raw, A. D., Yue, M., Jansen-West, K., Zhang, X., Prudencio, M., Chew, J., Cook, C. N., Daughrity, L. M., Tong, J., Song, Y., Pickles, S. R., Castanedes-Casey, M., Kurti, A., Rademakers, R., Oskarsson, B., Dickson, D. W., ... Petrucelli, L. (2018). Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Nature Medicine, 24(8), 1136-1142. https://doi.org/10.1038/s41591-018-0071-1

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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 = "Zhang, {Yong Jie} and Gendron, {Tania F.} and Ebbert, {Mark T.W.} and O{\textquoteright}Raw, {Aliesha D.} and Mei Yue and Karen Jansen-West and Xu Zhang and Mercedes Prudencio and Jeannie Chew and Cook, {Casey N.} and Daughrity, {Lillian M.} and Jimei Tong and Yuping Song and Pickles, {Sarah R.} and Monica Castanedes-Casey and Aishe Kurti and Rosa Rademakers and Bjorn Oskarsson and Dickson, {Dennis W.} and Wenqian Hu and Gitler, {Aaron D.} and Fryer, {John D.} and Leonard Petrucelli",

note = "Funding 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{\textquoteright}Aniello. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = aug,

day = "1",

doi = "10.1038/s41591-018-0071-1",

language = "English",

volume = "24",

pages = "1136--1142",

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Zhang, YJ, Gendron, TF, Ebbert, MTW, O’Raw, AD, Yue, M, Jansen-West, K, Zhang, X, Prudencio, M, Chew, J, Cook, CN, Daughrity, LM, Tong, J, Song, Y, Pickles, SR, Castanedes-Casey, M, Kurti, A, Rademakers, R, Oskarsson, B, Dickson, DW, Hu, W, Gitler, AD, Fryer, JD & Petrucelli, L 2018, 'Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis', Nature Medicine, vol. 24, no. 8, pp. 1136-1142. https://doi.org/10.1038/s41591-018-0071-1

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

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