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Gene-corrected Parkinson’s disease neurons show the A30P alpha-synuclein point mutation leads to reduced neuronal branching and function

View ORCID ProfilePeter A. Barbuti, Bruno FR. Santos, View ORCID ProfilePaul M. Antony, Francois Massart, Gérald Cruciani, Claire M. Dording, Lukas Pavelka, Yong-Jun Kwon, View ORCID ProfileRejko Krüger
doi: https://doi.org/10.1101/2020.11.05.369389
Peter A. Barbuti
1Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Luxembourg; (P.B.); (B.S.); (P.A.); (F.M.); (G.C.); (C.D.); (L.P.); (R.K.)
2Transversal Translational Medicine, Luxembourg Institute of Health, L-1445, Luxembourg
3Department of Neurology, Columbia University Irving Medical Center, 10032, New York, NY, USA
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  • For correspondence: peter.barbuti@uni.lu rejko.krüger@lih.lu peter.barbuti@uni.lu bruno.santos@uni.lu paul.antony@uni.lu francois.massart@uni.lu gerald.cruciani@uni.lu claire.dording@uni.lu lukas.pavelka@uni.lu rejko.krueger@uni.lu
Bruno FR. Santos
1Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Luxembourg; (P.B.); (B.S.); (P.A.); (F.M.); (G.C.); (C.D.); (L.P.); (R.K.)
2Transversal Translational Medicine, Luxembourg Institute of Health, L-1445, Luxembourg
4Disease Modeling and Screening Platform (DMSP), Luxembourg Institute of Systems Biomedicine, University of Luxembourg & Luxembourg Institute of Health, 6 avenue du Swing, L-4367, Belvaux, Luxembourg
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  • For correspondence: peter.barbuti@uni.lu bruno.santos@uni.lu paul.antony@uni.lu francois.massart@uni.lu gerald.cruciani@uni.lu claire.dording@uni.lu lukas.pavelka@uni.lu rejko.krueger@uni.lu
Paul M. Antony
1Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Luxembourg; (P.B.); (B.S.); (P.A.); (F.M.); (G.C.); (C.D.); (L.P.); (R.K.)
4Disease Modeling and Screening Platform (DMSP), Luxembourg Institute of Systems Biomedicine, University of Luxembourg & Luxembourg Institute of Health, 6 avenue du Swing, L-4367, Belvaux, Luxembourg
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  • For correspondence: peter.barbuti@uni.lu bruno.santos@uni.lu paul.antony@uni.lu francois.massart@uni.lu gerald.cruciani@uni.lu claire.dording@uni.lu lukas.pavelka@uni.lu rejko.krueger@uni.lu
Francois Massart
1Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Luxembourg; (P.B.); (B.S.); (P.A.); (F.M.); (G.C.); (C.D.); (L.P.); (R.K.)
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  • For correspondence: peter.barbuti@uni.lu bruno.santos@uni.lu paul.antony@uni.lu francois.massart@uni.lu gerald.cruciani@uni.lu claire.dording@uni.lu lukas.pavelka@uni.lu rejko.krueger@uni.lu
Gérald Cruciani
1Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Luxembourg; (P.B.); (B.S.); (P.A.); (F.M.); (G.C.); (C.D.); (L.P.); (R.K.)
4Disease Modeling and Screening Platform (DMSP), Luxembourg Institute of Systems Biomedicine, University of Luxembourg & Luxembourg Institute of Health, 6 avenue du Swing, L-4367, Belvaux, Luxembourg
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Claire M. Dording
1Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Luxembourg; (P.B.); (B.S.); (P.A.); (F.M.); (G.C.); (C.D.); (L.P.); (R.K.)
2Transversal Translational Medicine, Luxembourg Institute of Health, L-1445, Luxembourg
4Disease Modeling and Screening Platform (DMSP), Luxembourg Institute of Systems Biomedicine, University of Luxembourg & Luxembourg Institute of Health, 6 avenue du Swing, L-4367, Belvaux, Luxembourg
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Lukas Pavelka
1Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Luxembourg; (P.B.); (B.S.); (P.A.); (F.M.); (G.C.); (C.D.); (L.P.); (R.K.)
5Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Luxembourg
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Yong-Jun Kwon
4Disease Modeling and Screening Platform (DMSP), Luxembourg Institute of Systems Biomedicine, University of Luxembourg & Luxembourg Institute of Health, 6 avenue du Swing, L-4367, Belvaux, Luxembourg
6Department of Oncology, Luxembourg Institute of Health, L-3555, Dudelange, Luxembourg; (Y-J.K.)
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Rejko Krüger
1Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Luxembourg; (P.B.); (B.S.); (P.A.); (F.M.); (G.C.); (C.D.); (L.P.); (R.K.)
2Transversal Translational Medicine, Luxembourg Institute of Health, L-1445, Luxembourg
4Disease Modeling and Screening Platform (DMSP), Luxembourg Institute of Systems Biomedicine, University of Luxembourg & Luxembourg Institute of Health, 6 avenue du Swing, L-4367, Belvaux, Luxembourg
5Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Luxembourg
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Abstract

Parkinson’s disease is characterised by the degeneration of A9 dopaminergic neurons and the pathological accumulation of alpha-synuclein. In a patient-derived stem cell model, we have generated dopaminergic neurons from an individual harbouring the p.A30P SNCA mutation and compared those neurons against gene-corrected isogenic control cell lines. We have used confocal microscopy to assess the neuronal network, specifically segmenting dopaminergic neurons and have identified image-based phenotypes showing axonal impairment and reduced neurite branching. We show using multi-electrode array (MEA) technology that the neurons carrying the endogenous p.A30P alpha-synuclein mutation are functionally impaired and identified mitochondrial dysfunction as a pathogenic cellular phenotype. We report that against gene-corrected isogenic control cell lines the neurons carrying the p.A30P SNCA mutation have a deficit and are susceptible to the mitochondrial toxin and environmental pesticide Rotenone. Our data supports 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.

Competing Interest Statement

The authors have declared no competing interest.

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Posted November 06, 2020.
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Gene-corrected Parkinson’s disease neurons show the A30P alpha-synuclein point mutation leads to reduced neuronal branching and function
Peter A. Barbuti, Bruno FR. Santos, Paul M. Antony, Francois Massart, Gérald Cruciani, Claire M. Dording, Lukas Pavelka, Yong-Jun Kwon, Rejko Krüger
bioRxiv 2020.11.05.369389; doi: https://doi.org/10.1101/2020.11.05.369389
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Gene-corrected Parkinson’s disease neurons show the A30P alpha-synuclein point mutation leads to reduced neuronal branching and function
Peter A. Barbuti, Bruno FR. Santos, Paul M. Antony, Francois Massart, Gérald Cruciani, Claire M. Dording, Lukas Pavelka, Yong-Jun Kwon, Rejko Krüger
bioRxiv 2020.11.05.369389; doi: https://doi.org/10.1101/2020.11.05.369389

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