Sirtuins: double players in Huntington's disease

•SIRT1 activation by RESV-like compounds is beneficial in several HD models.•Nicotinamide also exerts neuroprotection in HD.•SIRT2 inhibition might counteract deregulated cholesterol metabolism in HD.•SIRT3 may regulate mitochondrial dysfunction induced by mHTT.

Sirtuins are a conserved family of NAD+-dependent class III lysine deacetylases, known to regulate longevity. In mammals, the sirtuin family has seven members (SIRT1–7), which vary in enzymatic activity, subcellular distribution and targets. Pharmacological and genetic modulation of SIRTs has been widely spread as a promising approach to slow aging and neurodegenerative processes. Huntington's disease (HD) is a neurodegenerative disorder linked to expression of polyglutamine-expanded huntingtin (HTT) protein for which there is still no disease-reversing treatment. Studies in different animal models provide convincing evidence that SIRT1 protects both cellular and animal models from mutant HTT toxicity, however controversial results were recently reported. Indeed, as a consequence of a variety of SIRT-activation pathways, either activation or inhibition of a specific SIRT appears to be neuroprotective. Therefore, this review summarizes the recent progress and knowledge in sirtuins (particularly SIRT1–3) and their implications for HD treatment.