ArticlePharmacological research2020
Synergistic activation of AMPK prevents from polyglutamine-induced toxicity in Caenorhabditis elegans.
Article in Pharmacological research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- Drug-Induced Reduction in 80Q Aggregates in aBiomedicines · 2026Article
- SIR-2.3/SIRT4 loss enhances proteostasis and neuronal resilience via AMPK-induced autophagy in Huntington's disease models.Cell communication and signaling : CCS · 2026Article
- Diverse Applications of the Anti-Diabetic Drug Metformin in Treating Human Disease.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Docosahexaenoic Acid (DHA) Supplementation in a Triglyceride Form Prevents from Polyglutamine-Induced Dysfunctions inInternational journal of molecular sciences · 2024Article
- Erucin, a Natural Isothiocyanate, Prevents Polyglutamine-Induced Toxicity inInternational journal of molecular sciences · 2024Article
- Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?International journal of molecular sciences · 2024Review
- Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans.Nature communications · 2023Article
- Structured Docosahexaenoic Acid (DHA) Enhances Motility and Promotes the Antioxidant Capacity of AgedCells · 2023Article
- Changes in lipid metabolism driven by steroid signalling modulate proteostasis in C. elegans.EMBO reports · 2023Article
- Mn(II) Quinoline Complex (4QMn) Restores Proteostasis and Reduces Toxicity in Experimental Models of Huntington's Disease.International journal of molecular sciences · 2022Article
- Actions of Metformin in the Brain: A New Perspective of Metformin Treatments in Related Neurological Disorders.International journal of molecular sciences · 2022Review
- Article
- Multiview motion tracking based on a cartesian robot to monitor Caenorhabditis elegans in standard Petri dishes.Scientific reports · 2022Article
- Neuroprotective Effect of IND1316, an Indole-Based AMPK Activator, in Animal Models of Huntington Disease.ACS chemical neuroscience · 2022Article
- Exploring the Pharmacological Potential of Metformin for Neurodegenerative Diseases.Frontiers in aging neuroscience · 2022Review
- Build-UPS and break-downs: metabolism impacts on proteostasis and aging.Cell death and differentiation · 2021Review
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
Expression of abnormally long polyglutamine (polyQ) tracks is the source of a range of dominant neurodegenerative diseases, such as Huntington disease. Currently, there is no treatment for this devastating disease, although some chemicals, e.g., metformin, have been proposed as therapeutic solutions. In this work, we show that metformin, together with salicylate, can synergistically reduce the number of aggregates produced after polyQ expression in Caenorhabditis elegans. Moreover, we demonstrate that incubation polyQ-stressed worms with low doses of both chemicals restores neuronal functionality. Both substances are pleitotropic and may activate a range of different targets. However, we demonstrate in this report that the beneficial effect induced by the combination of these drugs depends entirely on the catalytic action of AMPK, since loss of function mutants of aak-2/AMPKα2 do not respond to the treatment. To further investigate the mechanism of the synergetic activity of metformin/salicylate, we used CRISPR to generate mutant alleles of the scaffolding subunit of AMPK, aakb-1/AMPKβ1. In addition, we used an RNAi strategy to silence the expression of the second AMPKβ subunit in worms, namely aakb-2/AMPKβ2. In this work, we demonstrated that both regulatory subunits of AMPK are modulators of protein homeostasis. Interestingly, only aakb-2/AMPKβ2 is required for the synergistic action of metformin/salicylate to reduce polyQ aggregation. Finally, we showed that autophagy acts downstream of metformin/salicylate-related AMPK activation to promote healthy protein homeostasis in worms.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.