Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity

Yong Jie Zhang, Lin Guo, Patrick K. Gonzales, Tania F. Gendron, Yanwei Wu, Karen Jansen-West, Aliesha D. O’Raw, Sarah R. Pickles, Mercedes Prudencio, Yari Carlomagno, Mariam A. Gachechiladze, Connor Ludwig, Ruilin Tian, Jeannie Chew, Michael DeTure, Wen Lang Lin, Jimei Tong, Lillian M. Daughrity, Mei Yue, Yuping SongJonathan W. Andersen, Monica Castanedes-Casey, Aishe Kurti, Abhishek Datta, Giovanna Antognetti, Alexander McCampbell, Rosa Rademakers, Björn Oskarsson, Dennis W. Dickson, Martin Kampmann, Michael E. Ward, John D. Fryer, Christopher D. Link, James Shorter, Leonard Petrucelli

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

How hexanucleotide GGGGCC (G 4 C 2 ) repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G 4 C 2 repeats. The expression of green fluorescent protein–conjugated (PR) 50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1a (HP1a) liquid-phase disruptions, decreases in HP1a expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1a, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of C9orf72-associated FTD and ALS.

Original languageEnglish (US)
Article numbereaav2606
JournalScience
Volume363
Issue number6428
DOIs
StatePublished - Feb 15 2019

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Double-Stranded RNA
Heterochromatin
Proline
Arginine
Proteins
Histones
Methylation
Nuclear Lamina
Lamins
Gliosis
Dipeptides
Brain
Atrophy
Gene Expression
Neurons
DNA

ASJC Scopus subject areas

  • General

Cite this

Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity. / Zhang, Yong Jie; Guo, Lin; Gonzales, Patrick K.; Gendron, Tania F.; Wu, Yanwei; Jansen-West, Karen; O’Raw, Aliesha D.; Pickles, Sarah R.; Prudencio, Mercedes; Carlomagno, Yari; Gachechiladze, Mariam A.; Ludwig, Connor; Tian, Ruilin; Chew, Jeannie; DeTure, Michael; Lin, Wen Lang; Tong, Jimei; Daughrity, Lillian M.; Yue, Mei; Song, Yuping; Andersen, Jonathan W.; Castanedes-Casey, Monica; Kurti, Aishe; Datta, Abhishek; Antognetti, Giovanna; McCampbell, Alexander; Rademakers, Rosa; Oskarsson, Björn; Dickson, Dennis W.; Kampmann, Martin; Ward, Michael E.; Fryer, John D.; Link, Christopher D.; Shorter, James; Petrucelli, Leonard.

In: Science, Vol. 363, No. 6428, eaav2606, 15.02.2019.

Research output: Contribution to journalArticle

Zhang, YJ, Guo, L, Gonzales, PK, Gendron, TF, Wu, Y, Jansen-West, K, O’Raw, AD, Pickles, SR, Prudencio, M, Carlomagno, Y, Gachechiladze, MA, Ludwig, C, Tian, R, Chew, J, DeTure, M, Lin, WL, Tong, J, Daughrity, LM, Yue, M, Song, Y, Andersen, JW, Castanedes-Casey, M, Kurti, A, Datta, A, Antognetti, G, McCampbell, A, Rademakers, R, Oskarsson, B, Dickson, DW, Kampmann, M, Ward, ME, Fryer, JD, Link, CD, Shorter, J & Petrucelli, L 2019, 'Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity', Science, vol. 363, no. 6428, eaav2606. https://doi.org/10.1126/science.aav2606
Zhang, Yong Jie ; Guo, Lin ; Gonzales, Patrick K. ; Gendron, Tania F. ; Wu, Yanwei ; Jansen-West, Karen ; O’Raw, Aliesha D. ; Pickles, Sarah R. ; Prudencio, Mercedes ; Carlomagno, Yari ; Gachechiladze, Mariam A. ; Ludwig, Connor ; Tian, Ruilin ; Chew, Jeannie ; DeTure, Michael ; Lin, Wen Lang ; Tong, Jimei ; Daughrity, Lillian M. ; Yue, Mei ; Song, Yuping ; Andersen, Jonathan W. ; Castanedes-Casey, Monica ; Kurti, Aishe ; Datta, Abhishek ; Antognetti, Giovanna ; McCampbell, Alexander ; Rademakers, Rosa ; Oskarsson, Björn ; Dickson, Dennis W. ; Kampmann, Martin ; Ward, Michael E. ; Fryer, John D. ; Link, Christopher D. ; Shorter, James ; Petrucelli, Leonard. / Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity. In: Science. 2019 ; Vol. 363, No. 6428.
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abstract = "How hexanucleotide GGGGCC (G 4 C 2 ) repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G 4 C 2 repeats. The expression of green fluorescent protein–conjugated (PR) 50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1a (HP1a) liquid-phase disruptions, decreases in HP1a expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1a, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of C9orf72-associated FTD and ALS.",
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T1 - Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity

AU - Zhang, Yong Jie

AU - Guo, Lin

AU - Gonzales, Patrick K.

AU - Gendron, Tania F.

AU - Wu, Yanwei

AU - Jansen-West, Karen

AU - O’Raw, Aliesha D.

AU - Pickles, Sarah R.

AU - Prudencio, Mercedes

AU - Carlomagno, Yari

AU - Gachechiladze, Mariam A.

AU - Ludwig, Connor

AU - Tian, Ruilin

AU - Chew, Jeannie

AU - DeTure, Michael

AU - Lin, Wen Lang

AU - Tong, Jimei

AU - Daughrity, Lillian M.

AU - Yue, Mei

AU - Song, Yuping

AU - Andersen, Jonathan W.

AU - Castanedes-Casey, Monica

AU - Kurti, Aishe

AU - Datta, Abhishek

AU - Antognetti, Giovanna

AU - McCampbell, Alexander

AU - Rademakers, Rosa

AU - Oskarsson, Björn

AU - Dickson, Dennis W.

AU - Kampmann, Martin

AU - Ward, Michael E.

AU - Fryer, John D.

AU - Link, Christopher D.

AU - Shorter, James

AU - Petrucelli, Leonard

PY - 2019/2/15

Y1 - 2019/2/15

N2 - How hexanucleotide GGGGCC (G 4 C 2 ) repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G 4 C 2 repeats. The expression of green fluorescent protein–conjugated (PR) 50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1a (HP1a) liquid-phase disruptions, decreases in HP1a expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1a, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of C9orf72-associated FTD and ALS.

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