Alpha-synuclein induces the unfolded protein response in Parkinson's disease SNCA triplication iPSC-derived neurons

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Heman-Ackah, Sabrina M., Manzano, Raquel, Hoozemans, Jeroen J. M., Scheper, Wiep, Flynn, Rowan, Haerty, Wilfried ORCID: https://orcid.org/0000-0003-0111-191X, Cowley, Sally A., Bassett, Andrew R. and Wood, Matthew J. A. (2017) Alpha-synuclein induces the unfolded protein response in Parkinson's disease SNCA triplication iPSC-derived neurons. Human Molecular Genetics, 26 (22). pp. 4441-4450. ISSN 0964-6906

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Abstract

The recent generation of induced pluripotent stem cells (iPSCs) from a patient with Parkinson's disease (PD) resulting from triplication of the α-synuclein (SNCA) gene locus allows unprecedented opportunities to explore its contribution to the molecular pathogenesis of PD. We used the double-nicking CRISPR/Cas9 system to conduct site-specific mutagenesis of SNCA in these cells, generating an isogenic iPSC line with normalized SNCA gene dosage. Comparative gene expression analysis of neuronal derivatives from these iPSCs revealed an ER stress phenotype, marked by induction of the IRE1a/XBP1 axis of the unfolded protein response (UPR) and culminating in terminal UPR activation. Neuropathological analysis of post-mortem brain tissue demonstrated that pIRE1a is expressed in PD brains within neurons containing elevated levels of α-synuclein or Lewy bodies. Having used this pair of isogenic iPSCs to define this phenotype, these cells can be further applied in UPR-targeted drug discovery towards the development of disease-modifying therapeutics.

Item Type: Article
Additional Information: Funding Information: Cure Parkinson’s Trust and John Fell OUP Research Fund to S.M.H.-A., the John Fell OUP Research Fund to M.J.A.W. A.R.B, Wellcome Trust ISSF and contributions from the Departments of Pathology, Biochemistry, DPAG and Pharmacology. BBSRC, Institute Strategic Programme Grant [BB/J004669/1] (W.H.), University of North Carolina at Chapel Hill School of Medicine MD-PhD Program and NIH Oxford-Cambridge Scholars Program (S.M.H.-A.), ISAO, ZonMW, Alzheimer Nederland, and a Stellar grant from Janssen Pharmaceuticals (W.S.). The James Martin Stem Cell Facility (S.A.C., R.F.) receives financial support from the Wellcome Trust [WTISSF121302], the Oxford Martin School [LC0910-004] and EU IMI [StemBANCC]; the research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115439, resources of which are composed of financial contribution from the European Union’ Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. This publication reflects only the authors’ views, and neither the IMI JU nor EFPIA nor the European Commission are liable for any use that may be made of the information contained therein. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © The Author 2017. Published by Oxford University Press. All rights reserved.
Uncontrolled Keywords: molecular biology,genetics,genetics(clinical) ,/dk/atira/pure/subjectarea/asjc/1300/1312
Faculty \ School: Faculty of Science > School of Biological Sciences
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging
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Depositing User: LivePure Connector
Date Deposited: 15 Sep 2022 14:30
Last Modified: 19 Apr 2023 01:13
URI: https://ueaeprints.uea.ac.uk/id/eprint/88322
DOI: 10.1093/hmg/ddx331

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