Metformin inhibits RAN translation through PKR pathway and mitigates disease in <i>C9orf72</i> ALS/FTD mice
Tao Zu, Shu Guo, Olgert Bardhi, Daniel A. Ryskamp, Jian Li, Solaleh Khoramian Tusi, Avery Engelbrecht, Kelena Klippel, Paramita Chakrabarty, Lien Nguyen, Todd E. Golde, Nahum Sonenberg, Laura P.W. Ranum
Abstract
Significance 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.