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

Yong-Jie Zhang Lin Guo Patrick K Gonzales Tania F GendronYanwei WuKaren Jansen-WestAliesha D O'Raw Sarah R Pickles Mercedes Prudencio Yari CarlomagnoMariam A GachechiladzeConnor LudwigRuilin TianJeannie Chew Michael A DeTureWen-Lang LinJimei TongLillian M DaughrityMei YueYuping SongJonathan W AndersenMonica Castanedes CaseyAishe KurtiAbhishek DattaGiovanna AntognettiAlexander McCampbell Rosa Rademakers Björn E Oskarsson Gourisankar Ghosh Martin Edward Kampmann Michael Emmerson WardJohn D FryerChristopher D LinkJames Shorter Leonard Petrucelli

Published in: Science (New York, N.Y.) (2019)

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 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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