Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice
Open accessAbstract
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.
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Metformin also improves behaviour and pathology in ALS/FTD mice.
“Notably, metformin also improves behaviour and pathology in ALS/FTD mice.425”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [425]
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- Authors
- Zu, T., Guo, S., Bardhi, O., Ryskamp, D. A., Li, J., Khoramian Tusi, S., Engelbrecht, A., Klippel, K., Chakrabarty, P., Nguyen, L., Golde, T. E., Sonenberg, N., & Ranum, L. P. W.
- Affiliations
- University of Florida (US)
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL 32610;
- McGill University (CA)
- Corresponding author
- Sonenberg, Nahum
- Ranum, Laura P. W.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-07-20
- Volume
- 117
- Issue
- 31
- Pages
- 18591-18599
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7414156
- OpenAlex
- W3045265801
- Cited by
- 133
- References
- 44
- Citations by year
- 2026: 11 · 2025: 29 · 2024: 28 · 2023: 23 · 2022: 17 · 2021: 21 · 2020: 4
- FWCI
- 7.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship@McGill (McGill) (submittedVersion, cc-by-nc-nd)
- Funders
- Office of Extramural Research, National Institutes of Health (RO1 NS098819, R37 NS040389, PO1 NS058901)
- U.S. Department of Defense (W81XWH1910654)
- Myotonic Dystrophy Foundation (0000)
- Muscular Dystrophy Association (0000)
- Amyotrophic Lateral Sclerosis Association (0000)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- metformin, Ran protein, C9orf72, amyotrophic lateral sclerosis, frontotemporal dementia, PKR, double-stranded RNA-dependent protein kinase, repeat expansion, gene therapy, protein synthesis inhibition, neurodegenerative diseases
- MeSH terms
- C9orf72 Protein, Amyotrophic Lateral Sclerosis, Animals, Brain, Disease Models, Animal, Humans, Metformin, Mice, Transgenic, Protein Biosynthesis, Microsatellite Repeats, eIF-2 Kinase, Mice, Frontotemporal Dementia
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