Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine (polyQ) expansion in the huntingtin protein (Htt). Expression of the first exon of Htt containing an expanded polyQ produces neuronal dysfunction and axonal dystrophy in mechanosensory neurons in C. elegans (Parker et al., 2001). Genetic pathway analysis using this nematode model has emphasized a role for the longevity-promoting factor
daf-16/FoxO in the protection of neurons from expanded polyQ toxicity (Parker et al., 2005). Here, we investigated the role of AMP-activated protein kinase (AMPK), a well-known energy sensor involved in lifespan and health span extension, on neuronal dysfunction in expanded-polyQ nematodes and vulnerability to cell death in mutant Htt striatal cells (HdhQ111 knock-in mice). In C. elegans, activating this enzyme (
aak-2/AMPK) with metformin reduces the neuronal dysfunction caused by expanded polyQ expression. In contrast,
aak-2 mutants show enhanced neuronal impairment. In striatal cells from HdhQ111 knock-in mice, reducing AMPK levels by siRNA treatment enhances the susceptibility to cell death of mutant htt cells, and metformin treatment has the opposite effect. Additionally, overexpressing AMPK reduced striatal neurodegeneration in a rat lentiviral-based fragment model of HD pathogenesis. Collectively, our results suggest that AMPK activation has therapeutic potential to protect from neuron dysfunction and degeneration in HD.