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| Status |
Public on Feb 11, 2020 |
| Title |
Determining transcriptome changes in whole spinal cord of Gcn2-/-;GarsP278KY/+ adult mice [18-burgess-011] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
To determine transcriptome changes in adult spinal cord induced by the combined effect of having the GarsP278KY mutation while lacking GCN2 kinase .
How mutations in broadly expressed housekeeping genes lead to neurodegeneration in specific cell types remains unclear. Mutations in ubiquitously expressed tRNA synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth disease. Genetic evidence in mouse and Drosophila models suggests a neomorphic gain-of-function mechanism. Here, we use in vivo, cell-type-specific transcriptional and translational profiling of affected peripheral neurons to show that mutant tRNA synthetases impair translation and activate the integrated stress response (ISR) through the sensor kinase, GCN2. The chronic activation of the ISR contributes to the pathophysiology, and genetic deletion of Gcn2 alleviates the peripheral neuropathy. The activation of GCN2 by tRNA synthetase mutations indicates their neomorphic activity is still related to translation and suggests inhibiting GCN2 or the ISR as a therapeutic strategy.
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| Overall design |
Whole spinal cord RNA sequencing was performed on (1)Gcn2+/+;Gars+/+, (2)Gcn2-/-;Gars+/+, (3)Gcn2+/+;GarsP278KY/+, and (4)Gcn2-/-;GarsP278KY/+ 8 week-old mice and differential expression analysis was run.
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| Contributor(s) |
Spaulding EL, Burgess RW |
| Citation missing |
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| Submission date |
Feb 09, 2020 |
| Last update date |
Feb 13, 2020 |
| Contact name |
Abigail Tadenev |
| Organization name |
The Jackson Laboratory
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| Lab |
Dr. Robert Burgess
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| Street address |
600 Main St
|
| City |
Bar Harbor |
| State/province |
ME |
| ZIP/Postal code |
04609 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (24)
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| This SubSeries is part of SuperSeries: |
| GSE145006 |
Mutations in tRNA synthetases impair translation and activate the integrated stress response in inherited peripheral neuropathie |
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| Relations |
| BioProject |
PRJNA605658 |
| SRA |
SRP247872 |
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