Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease.
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.
Outeiro
Tiago Fleming
TF
Alzheimer's Research Unit, MGH, Harvard Medical School, CNY 114, 16th Street, Charlestown, MA 02129, USA.
Kontopoulos
Eirene
E
Altmann
Stephen M
SM
Kufareva
Irina
I
Strathearn
Katherine E
KE
Amore
Allison M
AM
Volk
Catherine B
CB
Maxwell
Michele M
MM
Rochet
Jean-Christophe
JC
McLean
Pamela J
PJ
Young
Anne B
AB
Abagyan
Ruben
R
Feany
Mel B
MB
Hyman
Bradley T
BT
Kazantsev
Aleksey G
AG
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*
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