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Published Online June 21, 2007
Science DOI: 10.1126/science.1143780

Reports

Submitted on April 13, 2007
Accepted on June 8, 2007

Sirtuin 2 Inhibitors Rescue {alpha}-Synuclein-Mediated Toxicity in Models of Parkinson's Disease

Tiago Fleming Outeiro 1, Eirene Kontopoulos 2, Steve Altman 3, Irina Kufareva 4, Katherine E. Strathearn 5, Allison M. Amore 3, Catherine B. Volk 5, Michele M. Maxwell 3, Jean-Christophe Rochet 5, Pamela J. McLean 1, Anne B. Young 3, Ruben Abagyan 4, Mel B. Feany 2, Bradley T. Hyman 1, Aleksey Kazantsev 3*

1 Alzheimer's Research Unit, MGH, Harvard Medical School, CNY 114, 16th Street, Charlestown, MA 02129, USA; MassGeneral Institute for Neurodegenerative Disease, MGH, Harvard Medical School, CNY 114, 16th Street, Charlestown, MA 02129, USA.
2 Harvard Medical School and Brigham and Women's Hospital, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Harvard New Research Building, Room 630, 77 Louis Pasteur Avenue, Boston, MA 02115, USA.
3 MassGeneral Institute for Neurodegenerative Disease, MGH, Harvard Medical School, CNY 114, 16th Street, Charlestown, MA 02129, USA.
4 Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
5 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907-2091, USA.

* To whom correspondence should be addressed.
Aleksey Kazantsev , E-mail: akazantsev{at}partners.org

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. Here, 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 siRNA 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.


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