title: Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological characterization of SIRT1 and SIRT2 pathways.
abstract: Acetylation homeostasis is thought to play a role in amyotrophic lateral sclerosis, and treatment with inhibitors of histone deacetylases has been considered a potential and attractive therapeutic approach, despite the lack of a thorough study of this class of proteins. In this study, we have considerably extended previous knowledge on the expression of 13 histone deacetylases in tissues (spinal cord and muscle) from mice carrying two different ALS-linked SOD1 mutations (G93A-SOD1 and G86R-SOD1). We have then focused on class III histone deacetylases SIRT1 and SIRT2 that are considered relevant in neurodegenerative diseases. SIRT1 decreases in the spinal cord, but increases in muscle during the progression of the disease, and a similar expression pattern is observed in the corresponding cell models (neuroblastoma and myoblasts). SIRT2 mRNA expression increases in the spinal cord in both G93A-SOD1 and G86R-SOD1 mice but protein expression is substantially unchanged in all the models examined. At variance with other sirtuin modulators (sirtinol, AGK2 and SRT1720), the well-known SIRT1 inhibitor Ex527 has positive effects on survival of neuronal cells expressing mutant SOD1, but this effect is neither mediated by SIRT1 inhibition nor by SIRT2 inhibition. These data call for caution in proposing sirtuin modulation as a target for treatment.
authors.affiliation: 1] Institute for Cell Biology and Neurobiology, CNR, Rome, Italy [2] Fondazione Santa Lucia IRCCS, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Valle
authors.affiliation: 1] Fondazione Santa Lucia IRCCS, Rome, Italy [2] Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Salvatori
authors.affiliation: 1] Fondazione Santa Lucia IRCCS, Rome, Italy [2] Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Gerbino
authors.affiliation: 1] Fondazione Santa Lucia IRCCS, Rome, Italy [2] Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Rossi
authors.affiliation: 1] INSERM U1118, Laboratoire de Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France [2] Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg, France.
authors.forename: L
authors.initials: L
authors.lastname: Palamiuc
authors.affiliation: 1] INSERM U1118, Laboratoire de Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France [2] Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg, France.
authors.forename: F
authors.initials: F
authors.lastname: René
authors.affiliation: 1] Fondazione Santa Lucia IRCCS, Rome, Italy [2] Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: M T
authors.initials: MT
authors.lastname: Carrì
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D004791:Enzyme Inhibitors; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C470545:Sirt1 protein, mouse; C418743:Sirt2 protein, mouse; D056564:Sirtuin 1; D056565:Sirtuin 2; D006655:Histone Deacetylases