Modeling Parkinson’s disease in midbrain-like organoids

Modeling Parkinson’s disease (PD) using advanced experimental in vitro models is a powerful tool to study disease mechanisms and to elucidate unexplored aspects of this neurodegenerative disorder. Here, we demonstrate that three-dimensional (3D) differentiation of expandable midbrain floor plate neu...

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Vydáno v:NPJ Parkinson's Disease Ročník 5; číslo 1; s. 5
Hlavní autoři: Smits, Lisa M., Reinhardt, Lydia, Reinhardt, Peter, Glatza, Michael, Monzel, Anna S., Stanslowsky, Nancy, Rosato-Siri, Marcelo D., Zanon, Alessandra, Antony, Paul M., Bellmann, Jessica, Nicklas, Sarah M., Hemmer, Kathrin, Qing, Xiaobing, Berger, Emanuel, Kalmbach, Norman, Ehrlich, Marc, Bolognin, Silvia, Hicks, Andrew A., Wegner, Florian, Sterneckert, Jared L., Schwamborn, Jens C.
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 05.04.2019
Nature Publishing Group
Témata:
631/136/532/2182
631/378/87
631/532/2064/2158
631/80
692/617/375/1718
Biomedical and Life Sciences
Biomedicine
Brain research
Brief Communication
Dopamine
Neurology
Neurons
Neurosciences
Parkinson's disease
ISSN:2373-8057, 2373-8057
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Shrnutí:Modeling Parkinson’s disease (PD) using advanced experimental in vitro models is a powerful tool to study disease mechanisms and to elucidate unexplored aspects of this neurodegenerative disorder. Here, we demonstrate that three-dimensional (3D) differentiation of expandable midbrain floor plate neural progenitor cells (mfNPCs) leads to organoids that resemble key features of the human midbrain. These organoids are composed of midbrain dopaminergic neurons (mDANs), which produce and secrete dopamine. Midbrain-specific organoids derived from PD patients carrying the LRRK2- G2019S mutation recapitulate disease-relevant phenotypes. Automated high-content image analysis shows a decrease in the number and complexity of mDANs in LRRK2- G2019S compared to control organoids. The floor plate marker FOXA2, required for mDAN generation, increases in PD patient-derived midbrain organoids, suggesting a neurodevelopmental defect in mDANs expressing LRRK2- G2019S. Thus, we provide a robust method to reproducibly generate 3D human midbrain organoids containing mDANs to investigate PD-relevant patho-mechanisms.
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ISSN:2373-8057
2373-8057
DOI:10.1038/s41531-019-0078-4