Midbrain organoids-development and applications in Parkinson's disease

Abstract

Human brain development is spatially and temporally complex. Insufficient access to human brain tissue and inadequacy of animal models has limited the study of brain development and neurodegenerative diseases. Recent advancements of brain organoid technology have created novel opportunities to model human-specific neurodevelopment and brain diseases. In this review, we discuss the use of brain organoids to model the midbrain and Parkinson's disease. We critically evaluate the extent of recapitulation of PD pathology by organoids and discuss areas of future development that may lead to the model to become a next-generation, personalized therapeutic strategy for PD and beyond.

Keywords: Parkinson; brain organoid; degeneration; disease modelling; dopamine neuron.

Figure 1

Timeline of key milestones in methods to derive midbrain dopaminergic neurons & MLOs (in blue). Timeline of key milestones in 2D neuronal and 3D organoid culture (in red)

Figure 2

Applications of midbrain-like organoids (MLOs), created with BioRender.com. MLOs are increasingly used to model midbrain development and midbrain-associated diseases. To improve the biological relevance of MLOs, methods including accelerating astrocytes development, vascularization of MLOs, incorporation of microglia and the making of multi-regional brain organoids are being explored. Parkinson’s disease (PD) modelling using MLOs is also becoming increasingly common. Current PD MLOs models can mimic pathologies including selective dopaminergic neuronal loss, ⍺-synuclein accumulation, electrophysiology alterations and LB-like inclusions. Despite MLO technology being relatively new, it has shown promise as a tool for therapeutic screening purposes. Created with Biorender.com.