ANALYSIS OF NEURONAL DIFFERENTIATION IN GENETIC FORMS OF PARKINSON’S DISEASE REVEALS A NEURODEVELOPMENTAL CONTRIBUTION

During the mammalian embryonic neurodevelopment, all neurons descend from neuroepithelial stem cells. Accumulating evidences indicate a contribution of neurodevelopmental processes to the vulnerability to diseases. Here, we elucidate such developmental contribution in the context of Parkinson’s disease by combining high content imaging approaches, single-cell RNA sequencing, 3D image analysis, and multifactorial functional mitochondrial readouts. We found that the prominent PD-associated LRRK2-G2019S mutation accelerates dopaminergic neuron differentiation, accompanied by a reduced viability, resulting in indistinguishable dopaminergic neuron quantities. Our data indicate that the unexpected dynamics is driven by LRRK2-G2019S-dependent aberrations in gene expression as well as mitochondrial health and biogenesis of the neuroepithelial stem cell population. We conclude that LRRK2-G2019S modifies the dynamics of dopaminergic neuron fate specification during development, what may constitute a predisposition to parts of the PD-associated clinical manifestations.