J Alex Parker et al. (2005) International Worm Meeting "Defining sirtuin activation as a neuroprotective strategy in models of Huntingtons Disease"

Helene Catoire, Cendrine Tourette, Emmanuel Lambert, J Alex Parker, Christian Neri, Salima Abderhamane, Margarita Arango

[International Worm Meeting, 2005]

Several reports suggest that the regulation of signal transduction and transcription is central to Huntingtons Disease (HD) pathogenesis and modification. We previously generated C. elegans transgenics expressing N-terminal huntingtin in touch receptor neurons, a model system that shows polyglutamine-dependent neuronal dysfunction and axonal dystrophy. We performed a genetic analysis of the cytotoxic pathways involved in this model. We found that Sir2 activation through increased sir-2.1 dosage or treatment with the sirtuin activator resveratrol specifically rescued early neuronal dysfunction phenotypes induced by mutant polyglutamines, two effects dependent on the transcription factor daf-16/FOXO. Additionally, resveratrol showed mutant polyglutamine-specific rescue of cell death in neuronal cells derived from HdhQ111 knock-in mice, an effect abolished by the co-incubation with sirtuin blockers. Sirtuin activation may thus protect against mutant polyglutamines. Additional studies will be needed to understand further the molecular basis of the neuroprotection elicited by sirtuin activation. Our data suggest that sirtuin activation may have therapeutic potential for HD and, potentially, other polyglutamine expansion neurodegenerative diseases.