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Human Molecular Genetics Advance Access originally published online on September 7, 2006
Human Molecular Genetics 2006 15(20):3012-3023; doi:10.1093/hmg/ddl243
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

{alpha}-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity

Eirene Kontopoulos, Jeffrey D. Parvin and Mel B. Feany*

Department of Pathology, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, 77 Avenue Louis Pasteur, New Research Building, Room 652, Boston, MA 02115, USA

* To whom correspondence should be addressed. Tel: +1 6175254405; Fax: +1 6175254422; Email: mel_feany{at}hms.harvard.edu

Received July 19, 2006; Revised August 28, 2006; Accepted September 4, 2006

{alpha}-synuclein is a neuronal protein implicated genetically in Parkinson's disease. {alpha}-synuclein localizes to the nucleus and presynaptic nerve terminals. Here we show that {alpha}-synuclein mediates neurotoxicity in the nucleus. Targeting of {alpha}-synuclein to the nucleus promotes toxicity, whereas cytoplasmic sequestration is protective in both cell culture and transgenic Drosophila. Toxicity of {alpha}-synuclein can be rescued by administration of histone deacetylase inhibitors in both cell culture and transgenic flies. {alpha}-synuclein binds directly to histones, reduces the level of acetylated histone H3 in cultured cells and inhibits acetylation in histone acetyltransferase assays. {alpha}-synuclein mutations that cause familial Parkinson's disease, A30P and A53T, exhibit increased nuclear targeting in cell culture. These findings implicate nuclear {alpha}-synuclein in promoting nigrostriatal degeneration in Parkinson's disease and encourage exploration of histone deacetylase inhibitors as potential therapies for the disorder.


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