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

Sabrina M Heman-Ackah, Raquel Manzano, Jeroen J M Hoozemans, Wiep Scheper, Rowan Flynn, Wilfried Haerty, Sally A Cowley, Andrew R Bassett, Matthew J A Wood

Research output: Contribution to JournalArticleAcademicpeer-review

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 IRE1α/XBP1 axis of the unfolded protein response (UPR) and culminating in terminal UPR activation. Neuropathological analysis of post-mortem brain tissue demonstrated that pIRE1α 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.

Original languageEnglish
Pages (from-to)4441-4450
Number of pages10
JournalHuman Molecular Genetics
Volume26
Issue number22
DOIs
Publication statusPublished - 15 Nov 2017

Funding

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.

FundersFunder number
EU IMI
James Martin Stem Cell Facility
Oxford Martin SchoolLC0910-004
National Institutes of Health
Cure Parkinson’s Trust
Janssen Pharmaceuticals
Wellcome TrustWTISSF121302
School of Medicine, University of North Carolina at Chapel Hill
Biotechnology and Biological Sciences Research CouncilBB/J004669/1
ZonMw
John Fell Fund, University of Oxford
Seventh Framework Programme
Internationale Stichting Alzheimer Onderzoek
Innovative Medicines Initiative115439

    Keywords

    • Journal Article

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