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

Author： Kontopoulos Eirene Parvin Jeffrey D. Feany Mel B.

ISSN： 1460-2083

Source： Human Molecular Genetics, Vol.15, Iss.20, 2006-10, pp. : 3012-3023

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

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.