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We thank the CGC, funded by the NIH Office of Research Infrastructure Programs (P40 OD010440), for worm strains. We also thank Andrew Fire for kindly providing the L4440 plasmid vector and the HT115 strain. We would also like to thank M Pilar Marin (Microscopy Unit of IIS-La Fe) and Carlos Mora Martinez (Institute of Biotechnology, University of Helsinki, Finland) for her kind help. RPVM is a Miguel Servet type II researcher (CPII16/00004) funded by Instituto de Salud Carlos III (ISCIII, Madrid, Spain). Grants from the ISCIII were used to perform this work (PI14/00949 and PI17/00011). All grants from ISCIII are co-financed by the European Development Regional Fund "A way to achieve Europe" (ERDF). JBY holds a grant from the Generalitat Valenciana and the European Social Fund (ACIF/2019/249). Some equipment used in this work has been funded in partnership between the Generalitat Valenciana (Conselleria de Sanitat I Salut Publica, Valencian Community, Spain) and European Funds (ERDF/FSE), through the call "Improvement of research infrastructures for rare diseases" CV FEDER 2014-2020. This work has been partially supported by a grant from the Fundacio Telemarato de la TV3 (Reference 559), which covered the work of MDS. The funds from the ISCIII are partially supported by the European Regional Development Fund. RPVM is also a Marie Curie fellow (CIG322034, EU). This work has been partially supported by a grant from the CIBERER (ACCI2016), a grant from the Fundacion Ramon Areces (CIVP19S8119) and an Ayuda Miguel Gil grant to RPVM (VII Convocatoria Ayudas a la Investigacion MHER, 2019).

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

Publicat a:Pharmacological Research. 161 105105- - 2020-11-01 161(), DOI: 10.1016/j.phrs.2020.105105

Autors: Gomez-Escribano, A P; Bono-Yague, J; Garcia-Gimeno, M A; Sequedo, M D; Hervas, D; Fornes-Ferrer, V; Torres-Sanchez, S C; Millan, J M; Sanz, P; Vazquez-Manrique, R P

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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/AMPK alpha 2 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/AMPK beta 1. In addition, we used an RNAi strategy to silence the expression of the second AMPK beta subunit in worms, namely aakb-2/AMPK beta 2. In this work, we demonstrated that both regulatory subunits of AMPK are modulators of protein homeostasis. Interestingly, only aakb-2/AMPK beta 2 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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