I20 Synergistic combinations of metformin and salicylate reduce polyglutamine toxicity in c. elegans

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Abstract

Activation of AMPK, a master regulator of the homeostasis of energy levels in the cell, has been shown to reduce toxicity induce both by mutant huntingtin and polyglutamines (polyQ) in both in vitro and in vivo models. Moreover, a cross-sectional study of the Enroll-HD database shows that metformin intake associates with better cognitive state of patients of Huntington’s disease (HD) which also are type 2 diabetics.

AMPK is at the center of a network of signaling pathways in which activation happens by allosteric stimulus, but also by direct phosphorylation. Once active, it phosphorylates a range of targets to regulate the levels of ATP. AMPK can be activated by nutrient deprivation, but also by stress of different kind, like for example polyQ-induced toxicity.

We sought to test whether synergistic combinations of potential AMPK activators, in a context of polyQ toxicity, may induce cellular protection in C. elegans. Analysis of different models of polyQ toxicity showed that some combinations of activators of AMPK are able to induce reduction in polyQ aggregates, and also to restore neuronal function in C. elegans.

Currently, we are investigating the mechanism by which this synergistic combination of substances restores normal cellular function, focusing on AMPK as a target. This enzyme is an obliged heterotrimer, composed by AMPKα, the catalytic subunit and two regulatory subunits, AMPKβ and AMPKγ. It is believed that allosteric activators bind AMPKβ, so we sought to test whether the activation of AMPK, and its neuroprotective activity, may depend on this subunit. To do so we have produced knock outs in the only two isoforms of AMPKβ present in the worm, aakb-1 and aakb-2, using CRISPR.

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