Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity.
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.
Kontopoulos
Eirene
E
Department of Pathology, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Parvin
Jeffrey D
JD
Feany
Mel B
MB
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*
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D051844:alpha-Synuclein