Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson's disease

Tiago Fleming Outeiro; Eirene Kontopoulos; Stephen M. Altmann; Irina Kufareva; Katherine E. Strathearn; Allison M. Amore; Catherine B. Volk; Michele M. Maxwell; Jean Christophe Rochet; Pamela J. McLean; Anne B. Young; Ruben Abagyan; Mel B. Feany; Bradley T. Hyman; Aleksey G. Kazantsev

doi:10.1126/science.1143780

Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson's disease

Tiago Fleming Outeiro, Eirene Kontopoulos, Stephen M. Altmann, Irina Kufareva, Katherine E. Strathearn, Allison M. Amore, Catherine B. Volk, Michele M. Maxwell, Jean Christophe Rochet, Pamela J. McLean, Anne B. Young, Ruben Abagyan, Mel B. Feany, Bradley T. Hyman, Aleksey G. Kazantsev

Neuroscience

Research output: Contribution to journal › Article › peer-review

797 Scopus citations

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 α-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson's disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued α-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.

Original language	English (US)
Pages (from-to)	516-519
Number of pages	4
Journal	Science
Volume	317
Issue number	5837
DOIs	https://doi.org/10.1126/science.1143780
State	Published - Jul 27 2007

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Outeiro, T. F., Kontopoulos, E., Altmann, S. M., Kufareva, I., Strathearn, K. E., Amore, A. M., Volk, C. B., Maxwell, M. M., Rochet, J. C., McLean, P. J., Young, A. B., Abagyan, R., Feany, M. B., Hyman, B. T., & Kazantsev, A. G. (2007). Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson's disease. Science, 317(5837), 516-519. https://doi.org/10.1126/science.1143780

Outeiro, TF, Kontopoulos, E, Altmann, SM, Kufareva, I, Strathearn, KE, Amore, AM, Volk, CB, Maxwell, MM, Rochet, JC, McLean, PJ, Young, AB, Abagyan, R, Feany, MB, Hyman, BT & Kazantsev, AG 2007, 'Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson's disease', Science, vol. 317, no. 5837, pp. 516-519. https://doi.org/10.1126/science.1143780

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title = "Sirtuin 2 inhibitors rescue α-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 α-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson's disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued α-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.",

author = "Outeiro, {Tiago Fleming} and Eirene Kontopoulos and Altmann, {Stephen M.} and Irina Kufareva and Strathearn, {Katherine E.} and Amore, {Allison M.} and Volk, {Catherine B.} and Maxwell, {Michele M.} and Rochet, {Jean Christophe} and McLean, {Pamela J.} and Young, {Anne B.} and Ruben Abagyan and Feany, {Mel B.} and Hyman, {Bradley T.} and Kazantsev, {Aleksey G.}",

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AU - Outeiro, Tiago Fleming

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AU - Kufareva, Irina

AU - Strathearn, Katherine E.

AU - Amore, Allison M.

AU - Volk, Catherine B.

AU - Maxwell, Michele M.

AU - Rochet, Jean Christophe

AU - McLean, Pamela J.

AU - Young, Anne B.

AU - Abagyan, Ruben

AU - Feany, Mel B.

AU - Hyman, Bradley T.

AU - Kazantsev, Aleksey G.

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AB - 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 α-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson's disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued α-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.

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Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson's disease

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