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

ABSTRACT: 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 ne

SUBMITTER: Oosterveen T 

PROVIDER: S-EPMC8581055 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature