@article{66b49d99a6e14dedac39feac6f0af0a2,
title = "Defects in mRNA Translation in LRRK2-Mutant hiPSC-Derived Dopaminergic Neurons Lead to Dysregulated Calcium Homeostasis",
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",
author = "Kim, {Jungwoo Wren} and Xiling Yin and Aanishaa Jhaldiyal and Khan, {Mohammed Repon} and Ian Martin and Zhong Xie and Tamara Perez-Rosello and Manoj Kumar and Leire Abalde-Atristain and Jinchong Xu and Li Chen and Eacker, {Stephen M.} and Surmeier, {D. James} and Ingolia, {Nicholas T.} and Dawson, {Ted M.} and Dawson, {Valina L.}",
note = "Funding Information: This work was supported by grants from the NIH ( P50 NS38377 ) and the JPB Foundation . T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. The authors acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital, The Johns Hopkins University School of Medicine, and the Foundation{\textquoteright}s Parkinson{\textquoteright}s Disease Program (M-2014). J.W.K. was supported by the Korea Foundation for Advanced Studies . I.M. was supported by NIH / NIA grant K01-01AG050718 . L.A.-A. was supported by a La Caixa Foundation grant . We thank Rachel Green and Mollie Meffert for discussions, Hyesoo Kim for iPSC generation, Joo Heon Shin for deep sequencing, and Thomas Gasser and Hans Sch{\"o}ler for isogenic iPSC lines. I.-Hsun Wu created Figure 1 D and our graphical abstract. Funding Information: This work was supported by grants from the NIH (P50 NS38377) and the JPB Foundation. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. The authors acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital, The Johns Hopkins University School of Medicine, and the Foundation's Parkinson's Disease Program (M-2014). J.W.K. was supported by the Korea Foundation for Advanced Studies. I.M. was supported by NIH/NIA grant K01-01AG050718. L.A.-A. was supported by a La Caixa Foundation grant. We thank Rachel Green and Mollie Meffert for discussions, Hyesoo Kim for iPSC generation, Joo Heon Shin for deep sequencing, and Thomas Gasser and Hans Sch?ler for isogenic iPSC lines. I.-Hsun Wu created Figure 1D and our graphical abstract. J.W.K. V.L.D. and T.M.D. formulated the hypothesis, organized the study, and wrote the manuscript with input from all authors; X.Y. designed, performed, and analyzed experiments from the isogenic lines; X.Y. and Z.X. performed Ca2+ imaging experiments; X.Y. and T.P.-R. conducted Ca2+ current recordings; A.J. and M.K. characterized iPSC lines and performed DA neuron differentiation; J.X. performed cortical neuron differentiation; J.W.K. X.Y. M.R.K. I.M. and L.A.-A. designed and performed biochemical studies and analyzed data; J.W.K. performed and analyzed ribosome profiling with the help of N.T.I. S.M.E. and M.R.K.; and D.J.S. initiated and supervised Ca2+ imaging and recording experiments with human DA neurons. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = oct,
day = "1",
doi = "10.1016/j.stem.2020.08.002",
language = "English (US)",
volume = "27",
pages = "633--645.e7",
journal = "Cell stem cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "4",
}