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

ABSTRACT: How hexanucleotide GGGGCC (G4C2) 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 G4C2 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 1? (HP1?) liquid-phase disruptions, decreases in HP1? expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1?, 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.

SUBMITTER: Zhang YJ 

PROVIDER: S-EPMC6524780 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Heterochromatin anomalies and double-stranded RNA accumulation underlie <i>C9orf72</i> poly(PR) toxicity.

Zhang Yong-Jie YJ   Guo Lin L   Gonzales Patrick K PK   Gendron Tania F TF   Wu Yanwei Y   Jansen-West Karen K   O'Raw Aliesha D AD   Pickles Sarah R SR   Prudencio Mercedes M   Carlomagno Yari Y   Gachechiladze Mariam A MA   Ludwig Connor C   Tian Ruilin R   Chew Jeannie J   DeTure Michael M   Lin Wen-Lang WL   Tong Jimei J   Daughrity Lillian M LM   Yue Mei M   Song Yuping Y   Andersen Jonathan W JW   Castanedes-Casey Monica M   Kurti Aishe A   Datta Abhishek A   Antognetti Giovanna G   McCampbell Alexander A   Rademakers Rosa R   Oskarsson Björn B   Dickson Dennis W DW   Kampmann Martin M   Ward Michael E ME   Fryer John D JD   Link Christopher D CD   Shorter James J   Petrucelli Leonard L  

Science (New York, N.Y.) 20190201 6428

How hexanucleotide GGGGCC (G<sub>4</sub>C<sub>2</sub>) repeat expansions in <i>C9orf72</i> 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<sub>4</sub>C<sub>2</sub> repeats. The expression of green fluorescent protein-conjugated (PR)<sub>50</sub> (a 50-repeat PR protein) throughout the mouse brain yielded progressive  ...[more]

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