title: Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease.
abstract: The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a role in aging. We identified a potent inhibitor of sirtuin 2 (SIRT2) and found that inhibition of SIRT2 rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson's disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued alpha-synuclein toxicity. Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson's disease. The results suggest a link between neurodegeneration and aging.
authors.affiliation: Alzheimer's Research Unit, MGH, Harvard Medical School, CNY 114, 16th Street, Charlestown, MA 02129, USA.
authors.forename: Tiago Fleming
authors.initials: TF
authors.lastname: Outeiro
authors.forename: Eirene
authors.initials: E
authors.lastname: Kontopoulos
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Altmann
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Strathearn
authors.forename: Allison M
authors.initials: AM
authors.lastname: Amore
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Volk
authors.forename: Michele M
authors.initials: MM
authors.lastname: Maxwell
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rochet
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McLean
authors.forename: Anne B
authors.initials: AB
authors.lastname: Young
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Mel B
authors.initials: MB
authors.lastname: Feany
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Aleksey G
authors.initials: AG
authors.lastname: Kazantsev
mesh_terms: D000107:Acetylation; D000818:Animals; D030801:Animals, Genetically Modified; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011487:Protein Conformation; D011804:Quinolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C521855:AGK2 compound; D005663:Furans; D011804:Quinolines; D034741:RNA, Small Interfering; D014404:Tubulin; D051844:alpha-Synuclein; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins; D004298:Dopamine