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

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.

SUBMITTER: Zu T 

PROVIDER: S-EPMC7414156 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Zu Tao T   Guo Shu S   Bardhi Olgert O   Ryskamp Daniel A DA   Li Jian J   Khoramian Tusi Solaleh S   Engelbrecht Avery A   Klippel Kelena K   Chakrabarty Paramita P   Nguyen Lien L   Golde Todd E TE   Sonenberg Nahum N   Ranum Laura P W LPW  

Proceedings of the National Academy of Sciences of the United States of America 20200720 31

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<sub>4</sub>C<sub>2</sub> 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 pro  ...[more]

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