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

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)633-645.e7
JournalCell stem cell
Volume27
Issue number4
DOIs
StatePublished - Oct 1 2020

Keywords

  • 5′ UTR
  • LRRK2
  • Parkinson's disease
  • RPS15
  • calcium homeostasis
  • ribosome profiling
  • translatome
  • uS19

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Kim, J. W., Yin, X., Jhaldiyal, A., Khan, M. R., Martin, I., Xie, Z., Perez-Rosello, T., Kumar, M., Abalde-Atristain, L., Xu, J., Chen, L., Eacker, S. M., Surmeier, D. J., Ingolia, N. T., Dawson, T. M., & Dawson, V. L. (2020). Defects in mRNA Translation in LRRK2-Mutant hiPSC-Derived Dopaminergic Neurons Lead to Dysregulated Calcium Homeostasis. Cell stem cell, 27(4), 633-645.e7. https://doi.org/10.1016/j.stem.2020.08.002