Toxic C9orf72 poly(PR) binds heterochromatin, disrupts HP1a and causes dsRNA accumulation

How G4C2 repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. Here, we report the first mouse model to express poly(PR), a dipeptide repeat protein synthesized from expanded G4C2 repeats. Expression of GFP-(PR)50 throughout the mouse brain yielded progressive brain atrophy, neuron5 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 abnormal histone methylation, lamin invaginations, decreases in HP1a expression, and disruptions of HP1a liquid phases. These aberrations of histone methylation, lamins and HP1a, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element10 expression and double-stranded RNA accumulation. Thus, we uncover new mechanisms by which poly(PR) contributes to c9FTD/ALS pathogenesis. Overall design: Examination of transcriptome profiles using RNA-seq on 3 month old mice expressing PR and GR polypetides with an AAV expression vector. The Poly(PR) analysis consisted of 7 mice expressing AAV-GFP-(PR)50 and 4 AAV-GFP harvest-matched controls. The Poly(GR) analysis consisted of 4 mice expressing AAV-GFP-(GR)100 and 4 AAV-GFP harvest-matched controls.

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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