Pluripotent stem cell derived dopaminergic subpopulations model the selective neuron degeneration in Parkinson's disease

In Parkinson's disease (PD), substantia nigra (SN) dopaminergic (DA) neurons degenerate, while related ventral tegmental area (VTA) DA neurons remain relatively unaffected. Here, we present a methodology that directs the differentiation of mouse and human pluripotent stem cells toward either SN-or VTA-like DA lineage and models their distinct vulnerabilities. We show that the level of WNT activity is critical for the induction of the SN-and VTA-lineage transcription factors Sox6 and Otx2, respectively. Both WNT signaling modulation and forced expression of these transcription factors can drive DA neurons toward the SN-or VTA-like fate. Importantly, the SN-like lineage enriched DA cultures recapitulate the selective sensitivity to mitochondrial toxins as observed in PD, while VTA-like neuron-enriched cultures are more resistant. Furthermore, a proteomics approach led to the identification of compounds that alter SN neuronal survival, demonstrating the utility of our strategy for disease modeling and drug discovery.

Automated summary

This study presents a methodology to direct the differentiation of mouse and human pluripotent stem cells into SN- or VTA-like DA neurons and explores their distinct vulnerabilities in the context of Parkinson's disease. The level of WNT activity is critical for the induction of lineage-specific transcription factors, Sox6 and Otx2, and modulation of WNT signaling can influence the fate of DA neurons. The SN-like lineage shows selective sensitivity to mitochondrial toxins, while the VTA-like neurons are more resistant, demonstrating the potential utility of these models for disease modeling and drug discovery.