title: Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity.
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, 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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Eirene
authors.initials: E
authors.lastname: Kontopoulos
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Parvin
authors.forename: Mel B
authors.initials: MB
authors.lastname: Feany
mesh_terms: D000107:Acetylation; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004330:Drosophila / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D030781:Organisms, Genetically Modified; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D051844:alpha-Synuclein