Modeling Parkinson’s disease in midbrain-like organoids

TLDR

In vitro models of Parkinson’s disease enable study of disease mechanisms and unexplored aspects of this neurodegenerative disorder. The study aims to provide a robust method to reproducibly generate 3D human midbrain organoids containing dopaminergic neurons for investigating Parkinson’s disease patho‑mechanisms. The authors differentiate expandable midbrain floor plate neural progenitor cells into 3D organoids that contain dopaminergic neurons and recapitulate key human midbrain features. The organoids contain dopamine‑producing dopaminergic neurons, and patient‑derived LRRK2‑G2019S organoids show reduced neuron number and complexity with increased FOXA2 expression, recapitulating Parkinson’s disease phenotypes.

Abstract

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.