PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons

Abstract Recent evidence suggests neurogenesis is on-going throughout life but the relevance of these findings for neurodegenerative disorders such as Parkinson’s disease (PD) is poorly understood. Biallelic PINK1 mutations cause early onset, Mendelian inherited PD. We studied the effect of PINK1 de...

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Autores principales:	Sarah J. Brown, Ibrahim Boussaad, Javier Jarazo, Julia C. Fitzgerald, Paul Antony, Marcus Keatinge, Janna Blechman, Jens C. Schwamborn, Rejko Krüger, Marysia Placzek, Oliver Bandmann
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f403a11711ed4072a52f7d7dcbd0861e
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spelling	oai:doaj.org-article:f403a11711ed4072a52f7d7dcbd0861e2021-12-02T11:45:01ZPINK1 deficiency impairs adult neurogenesis of dopaminergic neurons10.1038/s41598-021-84278-72045-2322https://doaj.org/article/f403a11711ed4072a52f7d7dcbd0861e2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84278-7https://doaj.org/toc/2045-2322Abstract Recent evidence suggests neurogenesis is on-going throughout life but the relevance of these findings for neurodegenerative disorders such as Parkinson’s disease (PD) is poorly understood. Biallelic PINK1 mutations cause early onset, Mendelian inherited PD. We studied the effect of PINK1 deficiency on adult neurogenesis of dopaminergic (DA) neurons in two complementary model systems. Zebrafish are a widely-used model to study neurogenesis in development and through adulthood. Using EdU analyses and lineage-tracing studies, we first demonstrate that a subset of ascending DA neurons and adjacent local-projecting DA neurons are each generated into adulthood in wild type zebrafish at a rate that decreases with age. Pink1-deficiency impedes DA neurogenesis in these populations, most significantly in early adult life. Pink1 already exerts an early effect on Th1+ progenitor cells rather than on differentiated DA neurons only. In addition, we investigate the effect of PINK1 deficiency in a human isogenic organoid model. Global neuronal differentiation in PINK1-deficient organoids and isogenic controls is similar, but PINK1-deficient organoids display impeded DA neurogenesis. The observation of impaired adult dopaminergic neurogenesis in Pink1 deficiency in two complementing model systems may have significant consequences for future therapeutic approaches in human PD patients with biallelic PINK1 mutations.Sarah J. BrownIbrahim BoussaadJavier JarazoJulia C. FitzgeraldPaul AntonyMarcus KeatingeJanna BlechmanJens C. SchwambornRejko KrügerMarysia PlaczekOliver BandmannNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sarah J. Brown Ibrahim Boussaad Javier Jarazo Julia C. Fitzgerald Paul Antony Marcus Keatinge Janna Blechman Jens C. Schwamborn Rejko Krüger Marysia Placzek Oliver Bandmann PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons
description	Abstract Recent evidence suggests neurogenesis is on-going throughout life but the relevance of these findings for neurodegenerative disorders such as Parkinson’s disease (PD) is poorly understood. Biallelic PINK1 mutations cause early onset, Mendelian inherited PD. We studied the effect of PINK1 deficiency on adult neurogenesis of dopaminergic (DA) neurons in two complementary model systems. Zebrafish are a widely-used model to study neurogenesis in development and through adulthood. Using EdU analyses and lineage-tracing studies, we first demonstrate that a subset of ascending DA neurons and adjacent local-projecting DA neurons are each generated into adulthood in wild type zebrafish at a rate that decreases with age. Pink1-deficiency impedes DA neurogenesis in these populations, most significantly in early adult life. Pink1 already exerts an early effect on Th1+ progenitor cells rather than on differentiated DA neurons only. In addition, we investigate the effect of PINK1 deficiency in a human isogenic organoid model. Global neuronal differentiation in PINK1-deficient organoids and isogenic controls is similar, but PINK1-deficient organoids display impeded DA neurogenesis. The observation of impaired adult dopaminergic neurogenesis in Pink1 deficiency in two complementing model systems may have significant consequences for future therapeutic approaches in human PD patients with biallelic PINK1 mutations.
format	article
author	Sarah J. Brown Ibrahim Boussaad Javier Jarazo Julia C. Fitzgerald Paul Antony Marcus Keatinge Janna Blechman Jens C. Schwamborn Rejko Krüger Marysia Placzek Oliver Bandmann
author_facet	Sarah J. Brown Ibrahim Boussaad Javier Jarazo Julia C. Fitzgerald Paul Antony Marcus Keatinge Janna Blechman Jens C. Schwamborn Rejko Krüger Marysia Placzek Oliver Bandmann
author_sort	Sarah J. Brown
title	PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons
title_short	PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons
title_full	PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons
title_fullStr	PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons
title_full_unstemmed	PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons
title_sort	pink1 deficiency impairs adult neurogenesis of dopaminergic neurons
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f403a11711ed4072a52f7d7dcbd0861e
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PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons

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