title: The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington's disease mouse models.
abstract: 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.
authors.affiliation: Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129-4404, USA.
authors.forename: Vanita
authors.initials: V
authors.lastname: Chopra
authors.forename: Luisa
authors.initials: L
authors.lastname: Quinti
authors.forename: Jinho
authors.initials: J
authors.lastname: Kim
authors.forename: Lorraine
authors.initials: L
authors.lastname: Vollor
authors.forename: K Lakshmi
authors.initials: KL
authors.lastname: Narayanan
authors.forename: Christina
authors.initials: C
authors.lastname: Edgerly
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Cipicchio
authors.forename: Molly A
authors.initials: MA
authors.lastname: Lauver
authors.forename: Soo Hyuk
authors.initials: SH
authors.lastname: Choi
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: Steven
authors.initials: S
authors.lastname: Hersch
authors.forename: Aleksey G
authors.initials: AG
authors.lastname: Kazantsev
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006816:Huntington Disease / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018696:Neuroprotective Agents / Q000494:pharmacology*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2