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An Isogenic Collection of Pluripotent Stem Cell Lines With Elevated alpha-Synuclein Expression Validated for Neural Induction and Cortical Neuron Differentiation

Natalwala, Ammar; Behbehani, Ranya; Yapom, Ratsuda; Kunath, Tilo; (2022) An Isogenic Collection of Pluripotent Stem Cell Lines With Elevated alpha-Synuclein Expression Validated for Neural Induction and Cortical Neuron Differentiation. Frontiers in Cell and Developmental Biology , 10 , Article 898560. 10.3389/fcell.2022.898560. Green open access

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Abstract

α-Synuclein (αSyn) is a small, disordered protein that becomes aggregated in Lewy body diseases, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Human induced pluripotent stem cells (hiPSCs) potentially provide a tractable disease model to monitor early molecular changes associated with PD/DLB. We and others have previously derived hiPSC lines from patients with duplication and triplication of the SNCA gene, encoding for αSyn. It is now recognised that to perform meaningful disease modelling with these hiPSC lines, it is critical to generate isogenic control cell lines that lack the disease causing mutations. In order to complement the existing and emerging hiPSC models for PD/DLB, we have generated an allelic series of αSyn over-expressing hESC lines on the same isogenic background. An unresolved question is whether pluripotent stem cell lines, with elevated levels of αSyn, can undergo efficient differentiation into dopaminergic and cortical neurons to model PD and DLB, respectively. We took advantage of our isogenic collection of hESC lines to determine if increased expression of αSyn affects neural induction and neuronal differentiation. Clonal hESC lines with significantly different levels of αSyn expression proliferated normally and maintained expression of pluripotent markers, such as OCT4. All cell lines efficiently produced PAX6+ neuroectoderm and there was no correlation between αSyn expression and neural induction efficiency. Finally, global transcriptomic analysis of cortical differentiation of hESC lines with low or high levels of αSyn expression demonstrated robust and similar induction of cortical neuronal expression profiles. Gene expression differences observed were unrelated to neural induction and neuronal differentiation. We conclude that elevated expression of αSyn in human pluripotent stem cells does not adversely affect their neuronal differentiation potential and that collections of isogenic cell lines with differing levels of αSyn expression are valid and suitable models to investigate synucleinopathies.

Type: Article
Title: An Isogenic Collection of Pluripotent Stem Cell Lines With Elevated alpha-Synuclein Expression Validated for Neural Induction and Cortical Neuron Differentiation
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fcell.2022.898560
Publisher version: https://doi.org/10.3389/fcell.2022.898560
Language: English
Additional information: Copyright © 2022 Natalwala, Behbehani, Yapom and Kunath. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: Science & Technology, Life Sciences & Biomedicine, Cell Biology, Developmental Biology, human pluripotent stem cells, alpha-synuclein, synucleinopathy, isogenic cell lines, cortical differentiation, neurogenesis, Parkinson's disease, STABLE TRANSGENE EXPRESSION, PARKINSONS-DISEASE, MICE LACKING, IDENTIFICATION, PROTEIN, FIBROBLASTS, CONVERSION, CHROMOSOME, SELECTION, CLONING
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/10152362
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