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A potent and selective sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of huntington's disease

  • Author(s): Smith, MR
  • Syed, A
  • Lukacsovich, T
  • Purcell, J
  • Barbaro, BA
  • Worthge, SA
  • Wei, SR
  • Pollio, G
  • Magnoni, L
  • Scali, C
  • Massai, L
  • Franceschini, D
  • Camarri, M
  • Gianfriddo, M
  • Diodato, E
  • Thomas, R
  • Gokce, O
  • Tabrizi, SJ
  • Caricasole, A
  • Landwehrmeyer, B
  • Menalled, L
  • Murphy, C
  • Ramboz, S
  • Luthi-Carter, R
  • Westerberg, G
  • Marsh, JL
  • et al.
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 inmodel organisms. However, agents that selectively target the disease-relevant HDACs have not been available. SirT1 (Sir2 in Drosophilamelanogaster) 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 selectivepharmacological inhibitionofDrosophila Sir2andmammalianSirT1usingthenovel inhibitor selisistat (selisistat; 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide)cansuppressHDpathologycausedby mutanthuntingtinexon1fragmentsinDrosophila,mammaliancellsandmice.WehavevalidatedSir2asthein 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 andmay also serve as a tool to better understand the downstream pathways of SirT1/Sir2 that may be critical for HD. © The Author 2014. Published by Oxford University Press. All rights reserved. Published by Oxford University Press. All rights reserved.

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