Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 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

doi:10.1073/pnas.2005748117

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

Proc Natl Acad Sci U S A. 2020 Aug 4;117(31):18591-18599. doi: 10.1073/pnas.2005748117. Epub 2020 Jul 20.

Authors

Tao Zu^{1

2

3}, Shu Guo^{1

2

3}, Olgert Bardhi^{1

2

3}, Daniel A Ryskamp^{1

2

3}, Jian Li^{1

2

3}, Solaleh Khoramian Tusi^{1

2

3}, Avery Engelbrecht^{1

2

3}, Kelena Klippel^{1

2

3}, Paramita Chakrabarty^{4

5}, Lien Nguyen^{1

2

3}, Todd E Golde^{4

5

6}, Nahum Sonenberg⁷, Laura P W Ranum^{8

2

3

6

9

10}

Affiliations

¹ Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL 32610.
² Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610.
³ Genetics Institute, University of Florida, Gainesville, FL 32610.
⁴ Center for Translation Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610.
⁵ Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610.
⁶ McKnight Brain Institute, University of Florida, Gainesville, FL 32610.
⁷ Department of Biochemistry, McGill University, Montreal, A3A 1A3, Canada; nahum.sonenberg@mcgill.ca ranum@ufl.edu.
⁸ Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL 32610; nahum.sonenberg@mcgill.ca ranum@ufl.edu.
⁹ Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610.
¹⁰ Norman Fixel Institute for Neurological Disease, University of Florida, Gainesville, FL 32608.

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.

Keywords: ALS/FTD; C9orf72; PKR; RAN translation; metformin.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amyotrophic Lateral Sclerosis / metabolism*
Animals
Brain / metabolism
Brain / pathology
C9orf72 Protein* / genetics
C9orf72 Protein* / metabolism
Disease Models, Animal
Frontotemporal Dementia / metabolism
Humans
Metformin / pharmacology*
Mice
Mice, Transgenic
Microsatellite Repeats / genetics
Protein Biosynthesis / drug effects*
eIF-2 Kinase* / genetics
eIF-2 Kinase* / metabolism

Substances

C9orf72 Protein
Metformin
eIF-2 Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding