During development, neuronal specification is attained through the function of certain developmental genes. Some of these genes encode transcription factors necessary for midbrain dopaminergic (DA) neuron development and are also important for the maintenance of the adult nervous system. Since the loss of DA neurons is responsible for the main symptoms of Parkinson's disease, scientists of the EU-funded DDPDGENES (Identification of genes important for human midbrain dopamine neuron development and Parkinson’s disease) project hypothesised that PD may involve a deregulation of the expression of genes implicated in DA neuron specification. To this end, they set out to analyse midbrain DA neuron genes and pathways that were differentially regulated in PD. Intriguingly, researchers identified five different molecular subtypes of DA neurons emerging from two embryonic types in both mouse and humans. Ventral midbrain development was found to be highly conserved among the two species, albeit with differences in key transcription factors. In another part of the project, scientists exploited induced pluripotent stem cells to generate DA neurons for transplantation or disease modelling. Molecular analysis of the resulting neurons indicated extensive heterogeneity and room for improvement of differentiation protocols. Towards this goal, scientists discovered selective LSD1 and HDAC inhibitors as potent modulators of DA neuron differentiation in vitro. Furthermore, a computational tool generated to assess the composition and quality of stem cell-derived DA neurons is anticipated to find application in the quality assurance of future cell transplantation clinical trials. Overall, the deliverables of the DDPDGENES study enhance our understanding of midbrain development and lay the foundation for the future transplantation of DA neurons as PD therapy.
Parkinson's disease, developmental genes, midbrain dopaminergic neuron, DDPDGENES, LSD1, HDAC inhibitor