Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 31, Pages 18591-18599Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2005748117
Keywords
metformin; RAN translation; C9orf72; PKR; ALS/FTD
Categories
Funding
- National Institutes of Health Grants [RO1 NS098819, R37NS040389, PO1-NS058901]
- Target ALS
- ALS Association
- Packard Center
- Myotonic Dystrophy Foundation
- Department of Defense Grant [W81XWH1910654]
- Muscular Dystrophy Association
- U.S. Department of Defense (DOD) [W81XWH1910654] Funding Source: U.S. Department of Defense (DOD)
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Repeat associated non-AUG (RAN) translation is found in a growing number of microsatellite expansion diseases, but the mechanisms remain unclear. We show that RAN translation is highly regulated by the double-stranded RNA-dependent protein kinase (PKR). In cells, structured CAG, CCUG, CAGG, and G(4)C(2) expansion RNAs activate PKR, which leads to increased levels of multiple RAN proteins. Blocking PKR using PKR-K296R, the TAR RNA binding protein or PKR-KO cells, reduces RAN protein levels. p-PKR is elevated in C9orf72 ALS/FTD human and mouse brains, and inhibiting PKR in C9orf72 BAC transgenic mice using AAV-PKR-K296R or the Food and Drug Administration (FDA)-approved drug metformin, decreases RAN proteins, and improves behavior and pathology. In summary, targeting PKR, including by use of metformin, is a promising therapeutic approach for C9orf72 ALS/FTD and other expansion diseases.
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