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.
Bibliographical noteFunding Information:
This study was supported by NIH grant 1U01NS066912-01A1 to A.G.K., S.H., R.J.F., and R.B.S. A.G.K., S.H., V.C., R.J.F., and R.B.S. designed the research; V.C., L.Q., L.V., L.K., J.K., C.E., P.M.C., and S.H.C. performed research; V.C., L.Q., and R.J.F. analyzed data; and A.G.K., V.C., S.H., R.J.F., and R.B.S. wrote the paper.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)