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

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

doi:10.1016/j.stem.2020.08.002

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

Cell Stem Cell. 2020 Oct 1;27(4):633-645.e7. doi: 10.1016/j.stem.2020.08.002. Epub 2020 Aug 25.

Authors

Jungwoo Wren Kim¹, Xiling Yin², Aanishaa Jhaldiyal³, Mohammed Repon Khan², Ian Martin², Zhong Xie⁴, Tamara Perez-Rosello⁴, Manoj Kumar², Leire Abalde-Atristain⁵, Jinchong Xu², Li Chen², Stephen M Eacker⁶, D James Surmeier⁴, Nicholas T Ingolia⁷, Ted M Dawson⁸, Valina L Dawson⁹

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA.
⁷ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁸ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA. Electronic address: tdawson@jhmi.edu.
⁹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA. Electronic address: vdawson@jhmi.edu.

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 Ca²⁺ regulation and to increased Ca²⁺ influx and elevated intracellular Ca²⁺ levels, a major contributor to PD pathogenesis. This study reveals a link between dysregulated translation control and Ca²⁺ homeostasis in G2019S LRRK2 human dopamine neurons, which potentially contributes to the progressive and selective dopaminergic neurotoxicity in PD.

Keywords: 5′ UTR; LRRK2; Parkinson’s disease; RPS15; calcium homeostasis; ribosome profiling; translatome; uS19.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Calcium
Dopaminergic Neurons / metabolism
Homeostasis
Humans
Induced Pluripotent Stem Cells* / metabolism
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
Mutation / genetics
Parkinson Disease* / genetics
Protein Biosynthesis

Substances

LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding