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

Autores de IIS La Fe

• Ana Pilar Gómez Escribano

  Autor

• José Bono Yagüe

  Autor

• María Dolores Sequedo Pérez

  Autor

• David Hervás Marín

  Autor

• Sara Carmen Torres Sánchez

  Autor

• 

  José María Millán Salvador

  Autor

• Rafael Vázquez Manrique

  Autor

Participantes ajenos a IIS La Fe

• García-Gimeno MA
• Fornés-Ferrer V
• Sanz P

Grupos

• Biomedicina Molecular, Celular y Genómica

  

  Leader

  José María Millán Salvador

• Unidad mixta de investigación en enfermedades raras (CIPF)

  

  Leader

  José María Millán Salvador

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/AMPKa2 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/AMPKß1. In addition, we used an RNAi strategy to silence the expression of the second AMPKß subunit in worms, namely aakb-2/AMPKß2. In this work, we demonstrated that both regulatory subunits of AMPK are modulators of protein homeostasis. Interestingly, only aakb-2/AMPKß2 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