Gene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function

Abstract Parkinson’s disease (PD) is characterised by the degeneration of A9 dopaminergic neurons and the pathological accumulation of alpha-synuclein. The p.A30P SNCA mutation generates the pathogenic form of the alpha-synuclein protein causing an autosomal-dominant form of PD. There are limited st...

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Main Authors:	Peter A. Barbuti, Jochen Ohnmacht, Bruno F. R. Santos, Paul M. Antony, François Massart, Gérald Cruciani, Claire M. Dording, Lukas Pavelka, Nicolas Casadei, Yong-Jun Kwon, Rejko Krüger
Format:	article
Language:	EN
Published:	Nature Portfolio 2021
Subjects:	Medicine R Science Q
Online Access:	https://doaj.org/article/fa5d1e8ffb404e52b22f63112205442d
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spelling	oai:doaj.org-article:fa5d1e8ffb404e52b22f63112205442d2021-11-14T12:19:46ZGene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function10.1038/s41598-021-01505-x2045-2322https://doaj.org/article/fa5d1e8ffb404e52b22f63112205442d2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01505-xhttps://doaj.org/toc/2045-2322Abstract Parkinson’s disease (PD) is characterised by the degeneration of A9 dopaminergic neurons and the pathological accumulation of alpha-synuclein. The p.A30P SNCA mutation generates the pathogenic form of the alpha-synuclein protein causing an autosomal-dominant form of PD. There are limited studies assessing pathogenic SNCA mutations in patient-derived isogenic cell models. Here we provide a functional assessment of dopaminergic neurons derived from a patient harbouring the p.A30P SNCA mutation. Using two clonal gene-corrected isogenic cell lines we identified image-based phenotypes showing impaired neuritic processes. The pathological neurons displayed impaired neuronal activity, reduced mitochondrial respiration, an energy deficit, vulnerability to rotenone, and transcriptional alterations in lipid metabolism. Our data describes for the first time the mutation-only effect of the p.A30P SNCA mutation on neuronal function, supporting the use of isogenic cell lines in identifying image-based pathological phenotypes that can serve as an entry point for future disease-modifying compound screenings and drug discovery strategies.Peter A. BarbutiJochen OhnmachtBruno F. R. SantosPaul M. AntonyFrançois MassartGérald CrucianiClaire M. DordingLukas PavelkaNicolas CasadeiYong-Jun KwonRejko KrügerNature 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 Peter A. Barbuti Jochen Ohnmacht Bruno F. R. Santos Paul M. Antony François Massart Gérald Cruciani Claire M. Dording Lukas Pavelka Nicolas Casadei Yong-Jun Kwon Rejko Krüger Gene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function
description	Abstract Parkinson’s disease (PD) is characterised by the degeneration of A9 dopaminergic neurons and the pathological accumulation of alpha-synuclein. The p.A30P SNCA mutation generates the pathogenic form of the alpha-synuclein protein causing an autosomal-dominant form of PD. There are limited studies assessing pathogenic SNCA mutations in patient-derived isogenic cell models. Here we provide a functional assessment of dopaminergic neurons derived from a patient harbouring the p.A30P SNCA mutation. Using two clonal gene-corrected isogenic cell lines we identified image-based phenotypes showing impaired neuritic processes. The pathological neurons displayed impaired neuronal activity, reduced mitochondrial respiration, an energy deficit, vulnerability to rotenone, and transcriptional alterations in lipid metabolism. Our data describes for the first time the mutation-only effect of the p.A30P SNCA mutation on neuronal function, supporting the use of isogenic cell lines in identifying image-based pathological phenotypes that can serve as an entry point for future disease-modifying compound screenings and drug discovery strategies.
format	article
author	Peter A. Barbuti Jochen Ohnmacht Bruno F. R. Santos Paul M. Antony François Massart Gérald Cruciani Claire M. Dording Lukas Pavelka Nicolas Casadei Yong-Jun Kwon Rejko Krüger
author_facet	Peter A. Barbuti Jochen Ohnmacht Bruno F. R. Santos Paul M. Antony François Massart Gérald Cruciani Claire M. Dording Lukas Pavelka Nicolas Casadei Yong-Jun Kwon Rejko Krüger
author_sort	Peter A. Barbuti
title	Gene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function
title_short	Gene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function
title_full	Gene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function
title_fullStr	Gene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function
title_full_unstemmed	Gene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function
title_sort	gene-corrected p.a30p snca patient-derived isogenic neurons rescue neuronal branching and function
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/fa5d1e8ffb404e52b22f63112205442d
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Gene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function

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