Cell:揭开帕金森病标志物的双面角色

2022-07-31 中国科学报 网络

Khurana及其同事的最初线索来自α-突触核蛋白毒性的酵母和果蝇模型,并通过对人类细胞,病人来源的神经元和人类遗传学的研究得到证实。

帕金森病(PD)的标志之一是在脑中积累称为α-突触核蛋白的蛋白质。二十多年来,α-突触核蛋白一直是研究人员、临床医生和制造商关注的焦点,但α-突触核蛋白的功能尚不明确。近日,由百瀚和妇女医院、哈佛干细胞研究所以及Broad研究所的研究人员领导的一项新研究为研究α-突触核蛋白的作用带来了希望,揭开了一个与PD和相关病症有关的新功能,研究结果发表在《细胞》(Cell)杂志上。

“我们的研究为一种已知处于帕金森病和相关疾病发展中心的蛋白质提供了新的见解。”论文通讯作者、百瀚和妇女医院及哈佛医学院神经病学系运动障碍科主任Vikram Khurana博士介绍说:“这是一种被当前疗法所靶向的蛋白质,但其功能一直难以捉摸,传统上认为α-突触核蛋白在与细胞膜的结合和被称为囊泡的运输结构中发挥了作用,但我们的研究表明α-突触核蛋白正在扮演着双重角色。”

双面的α-突触核蛋白 图源:百瀚和妇女医院

Khurana及其同事的最初线索来自α-突触核蛋白毒性的酵母和果蝇模型,并通过对人类细胞,病人来源的神经元和人类遗传学的研究得到证实。

研究小组发现,与囊泡相互作用的α-突触核蛋白的同一部分也与“P体”结构结合,P体是细胞中通过信使RNA(mRNA)调节基因表达的机制。在诱导多能干细胞衍生的神经元中,从具有α-突触核蛋白基因突变的帕金森病患者身上产生的P体,其生理结构和功能会丧失,并且mRNA调节异常。来自患者死后大脑的组织样本中也发生了同样的情况。人类基因分析支持了这些发现与疾病的相关性:在P体基因中积累突变的患者似乎患帕金森病的风险更高。

在该论文中,作者将α-突触核蛋白描述为一种“切换开关”,可调节两种非常不同的功能:囊泡运输和基因表达。在疾病状态下,这种平衡被打破。这些发现对PD治疗的发展具有潜在的意义。作者指出,需要更清楚哪些P体机制部件可能是治疗干预的最佳目标。正在进行的遗传研究旨在确定哪些患者可能最适合这种干预,以及这种新发现的途径在多大程度上有助于对整个帕金森病患者的疾病风险和疾病进展的研究。

论文主要作者、百瀚Ann Romney神经系统疾病中心神经病学系的Erinc Hallacli博士表示:“如果想要能够开发针对α-突触核蛋白的治疗方法,我们需要了解这种蛋白质的作用以及降低其水平或活性的潜在后果。这项研究提供了重要信息,以填补我们对该蛋白质的知识空白,这对临床转化非常有益。”

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    2023-03-16 维他命
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    2022-08-17 laiminchao

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