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.
Mesh Terms:
Acetylation, Animals, Brain, Cell Line, Tumor, Cell Nucleus, Drosophila, Histone Deacetylase Inhibitors, Histones, Humans, Mice, Neurons, Organisms, Genetically Modified, Parkinson Disease, alpha-Synuclein
Hum. Mol. Genet.
Date: Oct. 15, 2006
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