Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice
Abstract
Repeat-associated non-AUG (RAN) proteins accumulate in patient brains and contribute to a growing number of neurodegenerative diseases. There is an urgent need to understand why expression of these proteins does not require canonical or near-cognate AUG start codons and to develop ways to block RAN protein production. We show several types of repeat-expansion RNAs activate the double-stranded RNA-dependent protein kinase (PKR) pathway and that blocking PKR reduces RAN protein levels in cells. PKR is activated in C9orf72 ALS/FTD human and mouse brains and PKR inhibition using AAV-PKR-K296R or the FDA-approved drug metformin decreases RAN protein levels and improves disease in ALS/FTD mice. Targeting PKR using gene therapy or metformin are promising therapeutic approaches for C9orf72 ALS/FTD and other expansion diseases.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 20, 2020
- Source ID
- 10.1073/pnas.2005748117
Entities
People
- Avery Engelbrecht
- Daniel A Ryskamp
- Jiantao Li
- Kelena Klippel
- Laura Ranum
- Lien Nguyen
- Nahum Sonenberg
- Olgert Bardhi
- Paramita Chakrabarty
- Shu Guo
- Solaleh Khoramian Tusi
- Tao Zu
- Todd E. Golde
Organizations
- ALS Association
- McGill University
- Muscular Dystrophy Association
- Myotonic Dystrophy Foundation
- Office of Extramural Research
- United States Department of Defense
- University of Florida