期刊
FRONTIERS IN NEUROSCIENCE
卷 16, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fnins.2022.947927
关键词
G2019S LRRK2 mutation; Parkinson's disease; induced pluripotent stem cells; MPP+; inflammation
资金
- Jiangsu Provincial Key Research and Development Program [BE2018658]
- Health and Hygiene Scientific Research Project of Metallurgical Safety and Health Branch of The Chinese Society for Metals [JKWS202016]
- National Natural Science Foundation of China [82101333]
- project of Suzhou Science and Technology [SKJY2021088]
Induced pluripotent stem cells (iPSCs) can successfully mimic age-related diseases, such as Parkinson's disease (PD). In this study, we differentiated dopaminergic (DA) neurons from iPSCs of PD patients with the G2019S LRRK2 mutation and found morphological changes compared to control group. Furthermore, we observed that these mutated DA neurons were more vulnerable to damage, with higher rates of apoptosis and inflammatory response.
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)-1 beta, tumor necrosis factor-alpha, 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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