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| Status |
Public on May 29, 2019 |
| Title |
Toxic C9orf72 poly(PR) binds heterochromatin, disrupts HP1α and causes dsRNA accumulation |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 HP1α expression, and disruptions of HP1α liquid phases. These aberrations of histone methylation, lamins and HP1α, 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.
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| 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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| Contributor(s) |
Zhang Y, Guo L, Gonzales PK, Link CD, Shorter J, Petrucelli L |
| Citation(s) |
30765536 |
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| Submission date |
Jan 08, 2019 |
| Last update date |
May 29, 2019 |
| Contact name |
Christopher Link |
| Organization name |
University of Colorado Boulder
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| Department |
Integrative Physiology
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| Lab |
Link Lab
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| Street address |
1725 Pleasant st
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| City |
Boulder |
| State/province |
Colorado |
| ZIP/Postal code |
80309 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (19)
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| Relations |
| BioProject |
PRJNA513973 |
| SRA |
SRP178051 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE124834_RAW.tar |
5.8 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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