α-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity

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