title: The sirtuin-2 inhibitor AK7 is neuroprotective in models of Parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemia.
abstract: Sirtuin deacetylases regulate diverse cellular pathways and influence disease processes. Our previous studies identified the brain-enriched sirtuin-2 (SIRT2) deacetylase as a potential drug target to counteract neurodegeneration. In the present study, we characterize SIRT2 inhibition activity of the brain-permeable compound AK7 and examine the efficacy of this small molecule in models of Parkinson's disease, amyotrophic lateral sclerosis and cerebral ischemia. Our results demonstrate that AK7 is neuroprotective in models of Parkinson's disease; it ameliorates alpha-synuclein toxicity in vitro and prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion and dopaminergic neuron loss in vivo. The compound does not show beneficial effects in mouse models of amyotrophic lateral sclerosis and cerebral ischemia. These findings underscore the specificity of protective effects observed here in models of Parkinson's disease, and previously in Huntington's disease, and support the development of SIRT2 inhibitors as potential therapeutics for the two neurodegenerative diseases.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02129, United States of America.
authors.forename: Xiqun
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of NeuroDegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Goettingen, Waldweg 33, 37073, Goettingen, Germany.
authors.forename: Pauline
authors.initials: P
authors.lastname: Wales
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02129, United States of America.
authors.forename: Luisa
authors.initials: L
authors.lastname: Quinti
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02129, United States of America.
authors.forename: Fuxing
authors.initials: F
authors.lastname: Zuo
authors.affiliation: Department of Biochemistry, University of Bayreuth, Universitaetsstrasse 30, 95447, Bayreuth, Germany.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Moniot
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02129, United States of America.
authors.forename: Fanny
authors.initials: F
authors.lastname: Herisson
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02129, United States of America.
authors.forename: Nazifa Abdul
authors.initials: NA
authors.lastname: Rauf
authors.affiliation: Department of Chemistry, Department of Molecular Bioscience, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois, 60208-3113, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Department of Molecular Bioscience, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois, 60208-3113, United States of America.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02129, United States of America.
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02129, United States of America.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Maxwell
authors.affiliation: Department of Biochemistry, University of Bayreuth, Universitaetsstrasse 30, 95447, Bayreuth, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Steegborn
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02129, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schwarzschild
authors.affiliation: Department of NeuroDegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Goettingen, Waldweg 33, 37073, Goettingen, Germany.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02129, United States of America.
authors.forename: Aleksey G
authors.initials: AG
authors.lastname: Kazantsev
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects; D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage* / Q000494:pharmacology; D002545:Brain Ischemia / Q000503:physiopathology*; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism / Q000517:prevention & control*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: C000603971:3-(1-azepanylsulfonyl)-N-(3-bromphenyl)benzamide; D001549:Benzamides; D018696:Neuroprotective Agents; D054852:Small Molecule Libraries; D013449:Sulfonamides; D051844:alpha-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D056565:Sirtuin 2