Synergistic activation of AMPK prevents from polyglutamine-induced toxicity in Caenorhabditis elegans

Pharmacol Res. 2020 Nov:161:105105. doi: 10.1016/j.phrs.2020.105105. Epub 2020 Jul 30.

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.

Keywords: AMPK; Caenorhabditis elegans; Metformin; Salycilate; Synergy; polyQ toxicity.

Publication types

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

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Animals, Genetically Modified
  • Autophagy / drug effects
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Drug Synergism
  • Enzyme Activation
  • Enzyme Activators / pharmacology*
  • Metformin / pharmacology*
  • Mutation
  • Neurons / drug effects*
  • Neurons / enzymology
  • Neurons / pathology
  • Peptides / toxicity*
  • Protein Aggregates
  • Protein Aggregation, Pathological
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Proteostasis / drug effects*
  • Salicylates / pharmacology*

Substances

  • Caenorhabditis elegans Proteins
  • Enzyme Activators
  • Peptides
  • Protein Aggregates
  • Salicylates
  • polyglutamine
  • Metformin
  • Protein Serine-Threonine Kinases
  • AAK-2 protein, C elegans
  • AMP-Activated Protein Kinases