title: A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease.
abstract: Protein acetylation, which is central to transcriptional control as well as other cellular processes, is disrupted in Huntington's disease (HD). Treatments that restore global acetylation levels, such as inhibiting histone deacetylases (HDACs), are effective in suppressing HD pathology in model organisms. However, agents that selectively target the disease-relevant HDACs have not been available. SirT1 (Sir2 in Drosophila melanogaster) deacetylates histones and other proteins including transcription factors. Genetically reducing, but not eliminating, Sir2 has been shown to suppress HD pathology in model organisms. To date, small molecule inhibitors of sirtuins have exhibited low potency and unattractive pharmacological and biopharmaceutical properties. Here, we show that highly selective pharmacological inhibition of Drosophila Sir2 and mammalian SirT1 using the novel inhibitor selisistat (selisistat; 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) can suppress HD pathology caused by mutant huntingtin exon 1 fragments in Drosophila, mammalian cells and mice. We have validated Sir2 as the in vivo target of selisistat by showing that genetic elimination of Sir2 eradicates the effect of this inhibitor in Drosophila. The specificity of selisistat is shown by its effect on recombinant sirtuins in mammalian cells. Reduction of HD pathology by selisistat in Drosophila, mammalian cells and mouse models of HD suggests that this inhibitor has potential as an effective therapeutic treatment for human disease and may also serve as a tool to better understand the downstream pathways of SirT1/Sir2 that may be critical for HD.
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
authors.forename: Marianne R
authors.initials: MR
authors.lastname: Smith
authors.forename: Adeela
authors.initials: A
authors.lastname: Syed
authors.forename: Tamas
authors.initials: T
authors.lastname: Lukacsovich
authors.forename: Judy
authors.initials: J
authors.lastname: Purcell
authors.forename: Brett A
authors.initials: BA
authors.lastname: Barbaro
authors.forename: Shane A
authors.initials: SA
authors.lastname: Worthge
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wei
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pollio
authors.forename: Letizia
authors.initials: L
authors.lastname: Magnoni
authors.forename: Carla
authors.initials: C
authors.lastname: Scali
authors.forename: Luisa
authors.initials: L
authors.lastname: Massai
authors.forename: Davide
authors.initials: D
authors.lastname: Franceschini
authors.forename: Michela
authors.initials: M
authors.lastname: Camarri
authors.forename: Marco
authors.initials: M
authors.lastname: Gianfriddo
authors.forename: Enrica
authors.initials: E
authors.lastname: Diodato
authors.forename: Russell
authors.initials: R
authors.lastname: Thomas
authors.forename: Ozgun
authors.initials: O
authors.lastname: Gokce
authors.forename: S J
authors.initials: SJ
authors.lastname: Tabrizi
authors.forename: Andrea
authors.initials: A
authors.lastname: Caricasole
authors.forename: Bernard
authors.initials: B
authors.lastname: Landwehrmeyer
authors.forename: Liliana
authors.initials: L
authors.lastname: Menalled
authors.forename: Carol
authors.initials: C
authors.lastname: Murphy
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ramboz
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.forename: Goran
authors.initials: G
authors.lastname: Westerberg
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000008:administration & dosage*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; C447899:Sirt2 protein, Drosophila; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases