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. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Authors Oosterveen T, Garção P, Moles-Garcia E, Soleilhavoup C, Travaglio M, Sheraz S, Peltrini R, Patrick K, Labas V, Combes-Soia L, Marklund U, Hohenstein P, Panman L
Journal Stem cell reports
Publication Date 2021 Nov 9;16(11):2718-2735
PubMed 34678205
PubMed Central PMC8581055
DOI 10.1016/j.stemcr.2021.09.014

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