PARKINSON’S DISEASE EFFECT ON STRUCTURAL COMPLEXITY OF DOPAMINERGIC NEURON IN MIDBRAIN ORGANOIDS

Midbrain organoids are three-dimensional, self-organizing in vitro models derived from human pluripotent stem cells able to recapitulate key structural, cellular, and functional features of the developing human midbrain. Notably, they give rise to dopaminergic neurons, the cell population most prominently affected in Parkinson’s disease (PD). As such, midbrain organoids provide a physiologically relevant platform to quantitatively study PD-associated mechanisms such as dopaminergic neuron vulnerability, α-synuclein pathology, mitochondrial dysfunction.
In this light, we present a comparative morphometric analysis of dopaminergic neurons in midbrain organoids generated from cells of healthy donors and patients carrying a mutation linked to Parkinson’s Disease (PD). As such, dopaminergic cells were immunolabelled to reveal Tyrosine Hydroxylase (TH)-positive cells, acquired with a confocal microscope and segmented with a customized algorithm.
Morphometric descriptors including Sholl profiles and Strahler order were quantified to assess dendritic arborization and complexity, while cell volume was considered as a proxy for neuronal size. Our findings reveal that dopaminergic neurons extracted from PD organoids exhibit a reduction in structural complexity, showing a smaller cell size and a simplified dendritic architecture consistent with disease-associated degeneration of dopaminergic neurons. These results support the use of midbrain organoids as a useful in vitro platform for modeling Parkinson’s disease in vitro. Future studies combining morphology with other aspects (e.g., metabolism, functionality) will further clarify the effect of the disease at the microscale.