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。
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
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
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