Human midbrain organoids: a powerful tool for advanced Parkinson's disease modeling and therapy exploration

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder marked by the loss of dopaminergic neurons in the substantia nigra. Despite progress, the pathogenesis remains unclear. Human midbrain organoids (hMLOs) have emerged as a promising model for studying PD, drug screening, and potential treatments. This review discusses the development of hMLOs, their application in PD research, and current challenges in organoid construction, highlighting possible optimization strategies.

Fig. 1. Generation of hMLOs using human iPSCs.

Schematic diagrams illustrating the overall strategy to generate hMLOs. Differential interface contrast (DIC) images illustrate the typical morphology of cells at each stage. SBNC: SB431542, Noggin, and CHIR99021; SF: SHH-C25II and FGF8; BGAC: BDNF, GDNF, ascorbic acid, and db-cAMP. This image was independently created by us using Adobe Illustrator. All elements are original, and no third-party materials were used.

Fig. 2. Applications of hMLOs in Parkinson’s disease research.

Three main directions of hMLOs in PD research: PD model construction, PD toxicity predictions and PD treatment. PD model construction involves deriving iPSCs from PD patients or using gene-edited iPSCs to generate midbrain organoids, which are then used to investigate PD-related pathological changes, protein dysfunction, and neuronal degeneration. PD toxicity predictions explore the effects of oxidative stress-inducing compounds and selective toxins that target dopaminergic neurons. PD treatment research includes the extraction of neural stem cells (NSCs) from midbrain organoids for transplantation in mouse models and the selection of drugs that may provide therapeutic benefits. This image was independently created by us using Adobe Illustrator. All elements are original, and no third-party materials were used.