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

被引：411

作者：

Kontopoulos, Eirene ^{[1
]}

Parvin, Jeffrey D. ^{[1
]}

Feany, Mel B. ^{[1
]}

机构：

[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol,Program Neurosci, Boston, MA 02115 USA

来源：

HUMAN MOLECULAR GENETICS | 2006年 / 15卷 / 20期

关键词：

D O I：

10.1093/hmg/ddl243

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：3012 / 3023

页数：12

共 59 条

[1] Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system [J].