α-突触核蛋白的核易位机制及其功能

Mechanisms and Functions ofα-Synuclein Nuclear Translocation

α-突触核蛋白(alpha-synuclein,α-Syn)是一种脑内含量丰富的可溶性蛋白质,既能参与正常突触功能的维持和囊泡运输,又与多种神经退行性疾病有关,然而其确切的功能目前仍未完全清楚。已有研究表明,在生理条件下,α-突触核蛋白主要定位在细胞质中,少部分能定位在细胞核中,具有多种生物学功能。在帕金森病(Parkinson’s disease,PD)、阿尔兹海默病(Alzheimer’s disease,AD)患者大脑及氧化应激的细胞中,均发现α-突触核蛋白趋向于向细胞核中聚集。α-突触核蛋白核易位受到多种因素的精密调控,除自身氨基酸序列外,还受到其129位丝氨酸磷酸化(S129)水平、点突变(A53T,A30P,G51D)、细胞内Ca2+水平的影响,以及核输入蛋α(importin-α)、三结构域蛋白28(tripartite motif-containing protein 28,TRIM28)等多种蛋白质的精密调控,其异常的核易位则与细胞毒性相关。核易位的α-突触核蛋白能和组蛋白去乙酰化酶及组蛋白甲基化酶相互作用,从而改变组蛋白乙酰化和甲基化水平,最终影响染色质的稳定性。此外,α-突触核蛋白能与DNA相互作用,从而改变DNA构象、参与DNA损伤修复及基因表达调控。本文综述了α-突触核蛋白的结构特征,生理及病理条件下的细胞核内定位现象,详细的核易位机制及其在胞核中的功能研究进展,将有助于了解α-突触核蛋白生理功能及其在疾病发生发展中的作用。

Alpha-synuclein(α-Syn)is an abundant neuronal soluble protein.Though not yet completely understood,its role is related to synaptic function,vesicle trafficking and even many neurodegenerative disorders.Many studies show thatα-synuclein mainly located in the cytoplasm and also partly in the nucleus,playing important roles in a variety of complex biological progresses.α-synuclein has been shown to be distributed in the cell nucleus of the brain in PD,AD and cells under oxidative stress.Various modifiers precisely regulateα-synuclein nuclear translocation,including its own amino acid sequence,level of phosphorylation at Ser-129(S129),point mutations(A53T,A30P,G51D),intracellular Ca2+levels,and the nuclear transport protein importin-α,TRIM28 protein.Abnormal subcellular localization ofα-synuclein is involved in cytotoxicity.Nuclearα-synuclein modifies the demethylation and acetylation of histones by interacting with H3K9 methyltransferase and histone deacetylases(HDACs),respectively,which influence the stability of chromatin.In addition,the interaction betweenα-synuclein and DNA modulate the DNA damage response,conformational changes of DNA and regulation of gene expression.This article reviews the latest developments in physiological properties,performance of nuclear localization under physiological and pathological conditions,and detailed mechanisms of nuclear translocation and nuclear function ofα-synuclein in order to further understand the physiological function and its role on pathogenesis of diseases.