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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Animals
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Animals, Genetically Modified
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Cell Death / drug effects
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Cell Line, Tumor
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Cells, Cultured
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Disease Models, Animal
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Dopamine / physiology
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Dose-Response Relationship, Drug
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Drosophila melanogaster
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Furans / pharmacology*
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Humans
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Models, Molecular
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Neurons / cytology
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Neurons / drug effects
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Parkinson Disease / drug therapy*
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Parkinson Disease / metabolism
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Parkinson Disease / pathology
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Parkinson Disease / physiopathology*
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Protein Conformation
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Quinolines / pharmacology*
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RNA, Small Interfering / genetics
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Rats
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Sirtuin 1
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Sirtuin 2
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Sirtuins / antagonists & inhibitors*
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Sirtuins / chemistry
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Sirtuins / genetics
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Sirtuins / metabolism*
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Transfection
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Tubulin / metabolism
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alpha-Synuclein / genetics
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alpha-Synuclein / metabolism*
Substances
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AGK2 compound
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Furans
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Quinolines
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RNA, Small Interfering
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Tubulin
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alpha-Synuclein
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SIRT1 protein, human
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SIRT2 protein, human
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Sirtuin 1
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Sirtuin 2
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Sirtuins
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Dopamine