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G2019S LRRK2 Mutation Enhances MPP(+)-Induced Inflammation of Human Induced Pluripotent Stem Cells-Differentiated Dopaminergic Neurons

Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to mimic human diseases of related cell types, but it is unclear whether they can successfully mimic age-related diseases such as Parkinson’s disease (PD). We generated iPSCs lines from three patients with familial PD associat...

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Autores principales: Chen, Ying, Yin, Qing, Cheng, Xiao-Yu, Zhang, Jin-Ru, Jin, Hong, Li, Kai, Mao, Cheng-Jie, Wang, Fen, Bei, Hong-Zhe, Liu, Chun-Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9298923/
https://www.ncbi.nlm.nih.gov/pubmed/35873822
http://dx.doi.org/10.3389/fnins.2022.947927
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author Chen, Ying
Yin, Qing
Cheng, Xiao-Yu
Zhang, Jin-Ru
Jin, Hong
Li, Kai
Mao, Cheng-Jie
Wang, Fen
Bei, Hong-Zhe
Liu, Chun-Feng
author_facet Chen, Ying
Yin, Qing
Cheng, Xiao-Yu
Zhang, Jin-Ru
Jin, Hong
Li, Kai
Mao, Cheng-Jie
Wang, Fen
Bei, Hong-Zhe
Liu, Chun-Feng
author_sort Chen, Ying
collection PubMed
description Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to mimic human diseases of related cell types, but it is unclear whether they can successfully mimic age-related diseases such as Parkinson’s disease (PD). We generated iPSCs lines from three patients with familial PD associated with the G2019S mutation in the LRRK2 gene and one age-matched healthy individual (control). During long-term culture, dopaminergic (DA) neurons differentiated from iPSCs of G2019S LRRK2 PD patients exhibited morphological changes, including a reduced number of neurites and neurite arborization, which were not evident in DA neurons differentiated from control iPSCs. To mimic PD pathology in vitro, we used 1-methyl-4-phenylpyridium (MPP(+)) to damage DA neurons and found that DA neurons differentiated from patients with G2019S LRRK2 mutation significantly reduced the survival rate and increased apoptosis compared with the controls. We also found that the mRNA level of inflammatory factors [interleukin (IL)-1β, tumor necrosis factor-α, cyclooxygenase-2, IL-6, and inducible NO synthase] with G2019S LRRK2 mutation were higher than control group after exposure to MPP(+). Our study provides an in vitro model based on iPSCs that captures the patients’ genetic complexity and investigates the pathogenesis of familial PD cases in a disease-associated cell type.
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spelling pubmed-92989232022-07-21 G2019S LRRK2 Mutation Enhances MPP(+)-Induced Inflammation of Human Induced Pluripotent Stem Cells-Differentiated Dopaminergic Neurons Chen, Ying Yin, Qing Cheng, Xiao-Yu Zhang, Jin-Ru Jin, Hong Li, Kai Mao, Cheng-Jie Wang, Fen Bei, Hong-Zhe Liu, Chun-Feng Front Neurosci Neuroscience Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to mimic human diseases of related cell types, but it is unclear whether they can successfully mimic age-related diseases such as Parkinson’s disease (PD). We generated iPSCs lines from three patients with familial PD associated with the G2019S mutation in the LRRK2 gene and one age-matched healthy individual (control). During long-term culture, dopaminergic (DA) neurons differentiated from iPSCs of G2019S LRRK2 PD patients exhibited morphological changes, including a reduced number of neurites and neurite arborization, which were not evident in DA neurons differentiated from control iPSCs. To mimic PD pathology in vitro, we used 1-methyl-4-phenylpyridium (MPP(+)) to damage DA neurons and found that DA neurons differentiated from patients with G2019S LRRK2 mutation significantly reduced the survival rate and increased apoptosis compared with the controls. We also found that the mRNA level of inflammatory factors [interleukin (IL)-1β, tumor necrosis factor-α, cyclooxygenase-2, IL-6, and inducible NO synthase] with G2019S LRRK2 mutation were higher than control group after exposure to MPP(+). Our study provides an in vitro model based on iPSCs that captures the patients’ genetic complexity and investigates the pathogenesis of familial PD cases in a disease-associated cell type. Frontiers Media S.A. 2022-07-06 /pmc/articles/PMC9298923/ /pubmed/35873822 http://dx.doi.org/10.3389/fnins.2022.947927 Text en Copyright © 2022 Chen, Yin, Cheng, Zhang, Jin, Li, Mao, Wang, Bei and Liu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Chen, Ying
Yin, Qing
Cheng, Xiao-Yu
Zhang, Jin-Ru
Jin, Hong
Li, Kai
Mao, Cheng-Jie
Wang, Fen
Bei, Hong-Zhe
Liu, Chun-Feng
G2019S LRRK2 Mutation Enhances MPP(+)-Induced Inflammation of Human Induced Pluripotent Stem Cells-Differentiated Dopaminergic Neurons
title G2019S LRRK2 Mutation Enhances MPP(+)-Induced Inflammation of Human Induced Pluripotent Stem Cells-Differentiated Dopaminergic Neurons
title_full G2019S LRRK2 Mutation Enhances MPP(+)-Induced Inflammation of Human Induced Pluripotent Stem Cells-Differentiated Dopaminergic Neurons
title_fullStr G2019S LRRK2 Mutation Enhances MPP(+)-Induced Inflammation of Human Induced Pluripotent Stem Cells-Differentiated Dopaminergic Neurons
title_full_unstemmed G2019S LRRK2 Mutation Enhances MPP(+)-Induced Inflammation of Human Induced Pluripotent Stem Cells-Differentiated Dopaminergic Neurons
title_short G2019S LRRK2 Mutation Enhances MPP(+)-Induced Inflammation of Human Induced Pluripotent Stem Cells-Differentiated Dopaminergic Neurons
title_sort g2019s lrrk2 mutation enhances mpp(+)-induced inflammation of human induced pluripotent stem cells-differentiated dopaminergic neurons
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9298923/
https://www.ncbi.nlm.nih.gov/pubmed/35873822
http://dx.doi.org/10.3389/fnins.2022.947927
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