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LRRK2突变多巴胺能神经元中的mRNA翻译缺陷导致钙稳态失调
作者:小柯机器人 发布时间:2020/8/27 14:44:26

美国约翰·霍普金斯大学医学院Valina L. Dawson、Ted M. Dawson等研究人员合作发现,LRRK2突变多巴胺能神经元中的mRNA翻译缺陷导致钙稳态失调。该项研究成果于2020年8月254日在线发表在《细胞—干细胞》杂志上。

研究人员表示,亮氨酸丰富重复激酶2(LRRK2)中的G2019S突变是家族性帕金森氏病(PD)的常见原因。尽管蛋白质合成的改变如何导致人类神经元的神经变性仍未知,但这种突变会通过失调的蛋白质翻译导致多巴胺能神经变性。

通过核糖体分析,研究人员定义了从人诱导多能干细胞(hiPSC)衍生的LRRK2突变型多巴胺能神经元的翻译图谱。研究人员发现,在G2019S LRRK2神经元中,在5'非翻译区(UTR)中具有复杂二级结构的mRNA更有效地翻译。这导致参与Ca2+调控的多个基因翻译增强,并导致Ca2+内流增加和细胞内Ca2+水平升高,这是PD发病机理的主要因素。
 
这项研究揭示了G2019S LRRK2人多巴胺神经元中翻译控制失调与Ca2+稳态之间的联系,这可能会导致PD中进行性和选择性的多巴胺能神经毒性。
 
附:英文原文

Title: Defects in mRNA Translation in LRRK2-Mutant hiPSC-Derived Dopaminergic Neurons Lead to Dysregulated Calcium Homeostasis

Author: Jungwoo Wren Kim, Xiling Yin, Aanishaa Jhaldiyal, Mohammed Repon Khan, Ian Martin, Zhong Xie, Tamara Perez-Rosello, Manoj Kumar, Leire Abalde-Atristain, Jinchong Xu, Li Chen, Stephen M. Eacker, D. James Surmeier, Nicholas T. Ingolia, Ted M. Dawson, Valina L. Dawson

Issue&Volume: 2020-08-25

Abstract: The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of familialParkinson’s disease (PD). This mutation results in dopaminergic neurodegenerationvia dysregulated protein translation, although how alterations in protein synthesiscontribute to neurodegeneration in human neurons is not known. Here we define thetranslational landscape in LRRK2-mutant dopaminergic neurons derived from human inducedpluripotent stem cells (hiPSCs) via ribosome profiling. We found that mRNAs that havecomplex secondary structure in the 5′ untranslated region (UTR) are translated moreefficiently in G2019S LRRK2 neurons. This leads to the enhanced translation of multiplegenes involved in Ca2+ regulation and to increased Ca2+ influx and elevated intracellular Ca2+ levels, a major contributor to PD pathogenesis. This study reveals a link betweendysregulated translation control and Ca2+ homeostasis in G2019S LRRK2 human dopamine neurons, which potentially contributesto the progressive and selective dopaminergic neurotoxicity in PD.

DOI: 10.1016/j.stem.2020.08.002

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30398-2

期刊信息

Cell Stem Cell:《细胞—干细胞》,创刊于2007年。隶属于细胞出版社,最新IF:21.464
官方网址:https://www.cell.com/cell-stem-cell/home
投稿链接:https://www.editorialmanager.com/cell-stem-cell/default.aspx