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

• Published in: Cell reports (Cambridge) Vol. 2; no. 6; pp. 1492 - 1497
• Main Authors: Chopra, Vanita, Quinti, Luisa, Kim, Jinho, Vollor, Lorraine, Narayanan, K. Lakshmi, Edgerly, Christina, Cipicchio, Patricia M., Lauver, Molly A., Choi, Soo Hyuk, Silverman, Richard B., Ferrante, Robert J., Hersch, Steven, Kazantsev, Aleksey G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27-12-2012; Elsevier
• Subjects: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Histone Deacetylase Inhibitors - pharmacology; Huntington Disease - drug therapy; Huntington Disease - enzymology; Huntington Disease - genetics; Male; Mice; Mice, Mutant Strains; Neuroprotective Agents - pharmacology; Sirtuin 2 - antagonists & inhibitors; Sirtuin 2 - genetics; Sirtuin 2 - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.11.001

Inhibition 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.
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► 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
Currently, no treatment slows progression of Huntington’s disease (HD), a fatal neurodegenerative disorder characterized by progressive motor, psychiatric and cognitive decline. Previous studies revealed that inhibition of sirtuin 2 (SIRT2) deacetylase is neuroprotective in cellular, neuronal, and invertebrate HD models. Here, Kazantsev and colleagues demonstrate that a brain-permeable SIRT2 inhibitor ameliorates symptoms and brain pathology in two mouse models of HD, thereby providing preclinical validation of the SIRT2 target and the drug scaffold for development of HD therapeutics.