Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice.

Proceedings of the National Academy of Sciences of the United States of America
Tao ZuLaura P W Ranum

Abstract

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 G4C2 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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Citations

Jul 31, 2020·Proceedings of the National Academy of Sciences of the United States of America·Michael Rosbash
Sep 9, 2020·Endocrine Reviews·Traci E LaMoia, Gerald I Shulman
Dec 31, 2020·Human Molecular Genetics·Amrutha PattamattaLaura P W Ranum
Mar 9, 2021·Frontiers in Cellular Neuroscience·Alexander SchmitzSmita Saxena
Apr 2, 2021·Journal of Experimental Pharmacology·Marcello GiuntaAlberto Benussi
May 11, 2021·Frontiers in Cellular Neuroscience·Daniel A SolomonSarah Mizielinska
May 18, 2021·Frontiers in Aging Neuroscience·Nicolás W MartinezSoledad Matus
Jun 3, 2021·Biomedicines·Keith MaylYoun-Bok Lee
Jun 19, 2021·Nature Reviews. Molecular Cell Biology·Indranil MalikPeter K Todd
Jun 27, 2021·The Journal of Biological Chemistry·Yi-Ju TsengPhilip J Smaldino
Oct 23, 2021·Journal of Neurochemistry·Paulina TorresClaudio Hetz

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Methods Mentioned

BETA
transgenic
transfection
Protein blots

Software Mentioned

DigiGait

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