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

YongJie Zhang | Zendy; Lin Guo | Zendy; Patrick Gonzales | Zendy; Tania F. Gendron | Zendy; Yanwei Wu | Zendy; Karen JansenWest | Zendy; Aliesha D. O’Raw | Zendy; Sarah Pickles | Zendy; Mercedes Prudencio | Zendy; Yari Carlomagno | Zendy; Mariam A. Gachechiladze | Zendy; Connor H. Ludwig | Zendy; Ruilin Tian | Zendy; Jeannie Chew | Zendy; Michael DeTure | Zendy; Wen-Lang Lin | Zendy; Jimei Tong | Zendy; Lillian M. Daughrity | Zendy; Mei Yue | Zendy; Yuping Song | Zendy; Jonathan W. Andersen | Zendy; Monica CastanedesCasey | Zendy; Aishe Kurti | Zendy; Abhishek Datta | Zendy; Giovanna Antognetti | Zendy; Alexander McCampbell | Zendy; Rosa Rademakers | Zendy; Björn Oskarsson | Zendy; Dennis W. Dickson | Zendy; Martin Kampmann | Zendy; Michael E. Ward | Zendy; John Denis Fryer | Zendy; Christopher D. Link | Zendy; James Shorter | Zendy; Leonard Petrucelli | Zendy

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

Author(s) -

YongJie Zhang,

Lin Guo,

Patrick Gonzales,

Tania F. Gendron,

Yanwei Wu,

Karen JansenWest,

Aliesha D. O’Raw,

Sarah Pickles,

Mercedes Prudencio,

Yari Carlomagno,

Mariam A. Gachechiladze,

Connor H. Ludwig,

Ruilin Tian,

Jeannie Chew,

Michael DeTure,

Wen-Lang Lin,

Jimei Tong,

Lillian M. Daughrity,

Mei Yue,

Yuping Song,

Jonathan W. Andersen,

Monica CastanedesCasey,

Aishe Kurti,

Abhishek Datta,

Giovanna Antognetti,

Alexander McCampbell,

Rosa Rademakers,

Björn Oskarsson,

Dennis W. Dickson,

Martin Kampmann,

Michael E. Ward,

John Denis Fryer,

Christopher D. Link,

James Shorter,

Leonard Petrucelli

Publication year - 2019

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.aav2606

Subject(s) - c9orf72 , trinucleotide repeat expansion , frontotemporal dementia , amyotrophic lateral sclerosis , heterochromatin , biology , microbiology and biotechnology , open reading frame , gene expression , gene , genetics , chromosome , dementia , medicine , disease , pathology , peptide sequence , allele

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 1α (HP1α) liquid-phase disruptions, decreases in HP1α expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1α, 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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