Verified Commit 9e891b5b authored by Yohan Jarosz's avatar Yohan Jarosz 🐶
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title: The Parkinson’s disease associated mutation LRRK2-G2019S alters 2 dopaminergic differentiation dynamics via NR2F1
permalink: /frozen/y9k6-xa72
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{% rtitle The Parkinson’s disease associated mutation LRRK2-G2019S alters 2 dopaminergic differentiation dynamics via NR2F1 %}
Increasing evidence suggests that neurodevelopmental alterations might contribute to increase the susceptibility to develop neurodegenerative diseases later in life. We investigated the occurrence of developmental abnormalities in dopaminergic neurons in a model of Parkinson’s disease (PD). We monitored over time the differentiation of human patient-specific neuroepithelial stem cells (NESCs) into dopaminergic neurons. Using high-throughput image analyses and single-cell RNA-sequencing, we observed that the PD-associated LRRK2-G2019S mutation alters the initial phase of neuronal differentiation by accelerating cell cycle exit with a concomitant increase in cell death. We identified the NESC-specific core regulatory circuit and a molecular mechanism underlying the observed phenotypes. The expression of NR2F1, a key transcription factor involved in neurogenesis, decreased in LRRK2-G2019S NESCs, neurons, and midbrain organoids compared to controls. We also observed accelerated dopaminergic differentiation in vivo in NR2F1 deficient mouse embryos. This suggests a novel pathogenic mechanism involving the LRRK2-G2019S mutation, where the dynamics of dopaminergic differentiation are modified via NR2F1.
permalink: [doi:10.17881/y9k6-xa72](https://doi.org/10.17881/y9k6-xa72)
{% endrtitle %}
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