Abstract: Parkinson’s disease (PD) is a common neurodegenerative disorder affecting millions of people worldwide. The hallmark of PD is the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta region of the ventral midbrain (VM) and inclusion of Lewy bodies. PD presents as both idiopathic and genetic cases, complicating its study. Current pre-clinical models, while insightful, face limitations that highlight the need for more human-relevant models. Brain organoids have revolutionized disease modeling, offering a humanized 3D system that mimics brain regions such as the VM. VM organoids, though promising, encounter challenges in reproducibility and scalability, hindering the study of inter-individual genetic variations.
In this study we develop a model where multiple individuals are represented, creating a multi-donor VM organoid “mosaic VM organoid”. Following this we aim to create a mosaic organoid where multiple donors affected by genetic PD would be represented in a single organoid, reducing the variability and enabling patient-specific pathology screening. Utilizing genetic demultiplexing, we can observe at single-cell level effects on development and stress responses of individual cell lines with different genetic backgrounds. Successful generation of mosaic brain organoids would take disease modeling and drug screening to a new level, ultimately leading development of personalized therapies.
