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Human Molecular Genetics Advance Access published online on September 7, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl243
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received July 19, 2006
Revised August 28, 2006
Accepted September 4, 2006

Article

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

Eirene Kontopoulos 1, Jeffrey D. Parvin 1, and Mel B. Feany 1 *

1 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

* To whom correspondence should be addressed.
Mel B. Feany, E-mail: mel_feany{at}hms.harvard.edu


  Abstract

{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, while 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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