The Sirtuin 2 Inhibitor AK-7 Is Neuroprotective in Huntington’s Disease Mouse Models

SummaryInhibition of sirtuin 2 (SIRT2) deacetylase mediates protective effects in cell and invertebrate models of Parkinson’s disease and Huntington’s disease (HD). Here we report the in vivo efficacy of a brain-permeable SIRT2 inhibitor in two genetic mouse models of HD. Compound treatment resulted in improved motor function, extended survival, and reduced brain atrophy and is associated with marked reduction of aggregated mutant huntingtin, a hallmark of HD pathology. Our results provide preclinical validation of SIRT2 inhibition as a potential therapeutic target for HD and support the further development of SIRT2 inhibitors for testing in humans.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► Sirtuin 2 (SIRT2) inhibition is neuroprotective in two HD mouse models
► SIRT2 inhibitor treatment markedly reduces huntingtin aggregates in HD mouse brain
► SIRT2 is a promising therapeutic target for neurological protein aggregation disorders