Defects in MRNA Translation in LRRK2-Mutant HiPSC-Derived Dopaminergic Neurons Lead to Dysregulated Calcium Homeostasis

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2020 Aug 27

PMID 32846140

Citations 26

Authors

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

Affiliations

Soon will be listed here.

Abstract

The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of familial Parkinson's disease (PD). This mutation results in dopaminergic neurodegeneration via dysregulated protein translation, although how alterations in protein synthesis contribute to neurodegeneration in human neurons is not known. Here we define the translational landscape in LRRK2-mutant dopaminergic neurons derived from human induced pluripotent stem cells (hiPSCs) via ribosome profiling. We found that mRNAs that have complex secondary structure in the 5' untranslated region (UTR) are translated more efficiently in G2019S LRRK2 neurons. This leads to the enhanced translation of multiple genes involved in Ca regulation and to increased Ca influx and elevated intracellular Ca levels, a major contributor to PD pathogenesis. This study reveals a link between dysregulated translation control and Ca homeostasis in G2019S LRRK2 human dopamine neurons, which potentially contributes to the progressive and selective dopaminergic neurotoxicity in PD.

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