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

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19 Scopus citations

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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Zhang, Y. J., Guo, L., Gonzales, P. K., Gendron, T. F., Wu, Y., Jansen-West, K., O’Raw, A. D., Pickles, S. R., Prudencio, M., Carlomagno, Y., Gachechiladze, M. A., Ludwig, C., Tian, R., Chew, J., DeTure, M., Lin, W. L., Tong, J., Daughrity, L. M., Yue, M., ... Petrucelli, L. (2019). Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity. Science, 363(6428), [eaav2606]. https://doi.org/10.1126/science.aav2606