| Literature DB >> 30765536 |
Yong-Jie Zhang1,2, Lin Guo3, Patrick K Gonzales4, Tania F Gendron1,2, Yanwei Wu1, Karen Jansen-West1, Aliesha D O'Raw1, Sarah R Pickles1, Mercedes Prudencio1,2, Yari Carlomagno1, Mariam A Gachechiladze5, Connor Ludwig6, Ruilin Tian6, Jeannie Chew1,2, Michael DeTure1,2, Wen-Lang Lin1, Jimei Tong1, Lillian M Daughrity1, Mei Yue1, Yuping Song1, Jonathan W Andersen1, Monica Castanedes-Casey1, Aishe Kurti1, Abhishek Datta7, Giovanna Antognetti7, Alexander McCampbell8, Rosa Rademakers1,2, Björn Oskarsson9, Dennis W Dickson1,2, Martin Kampmann6, Michael E Ward5, John D Fryer1,2, Christopher D Link4, James Shorter3, Leonard Petrucelli10,2.
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 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.Entities:
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Year: 2019 PMID： 30765536 PMCID： PMC6524780 DOI： 10.1126/science.aav2606
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728