Abstract
Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson's disease (PD), but neuronal cultures are confounded by asynchronous and heterogeneous appearance of disease phenotypes in vitro. Using high-resolution, single-cell transcriptomic analyses of iPSC-derived dopamine neurons carrying the GBA-N370S PD risk variant, we identified a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Pseudotime analysis of genes differentially expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with HDAC4-modulating compounds upregulated genes early in the DE axis and corrected PD-related cellular phenotypes. Our study demonstrates how single-cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.
| Original language | English |
|---|---|
| Journal | Cell Stem Cell |
| Volume | 24 |
| Issue number | 1 |
| Pages (from-to) | 93-106.e6 |
| Number of pages | 14 |
| ISSN | 1934-5909 |
| DOIs | |
| Publication status | Published - 03.01.2019 |
Funding
The work was supported by the Monument Trust Discovery Award from Parkinson's UK . C.W. was supported by the Medical Research Council, UK . The Oxford Martin School ( LC0910-004 ) and the Wellcome Trust ( WTISSF121302 ) provide core support to the James Martin Stem Cell Facility within the Sir William Dunn School of Pathology (S.A.C.). The OPDC Discovery cohort was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford and the Dementia and Neurodegenerative Diseases Research Network (DeNDRoN). Single-cell transcriptomics at the Oxford Genomics Centre was supported by a Wellcome Trust core grant to the Wellcome Centre for Human Genetics, reference 090532/Z/09/Z . We also thank Christine Klein (Lübeck) for clinical expertise in PD and Uroosa Chughtai (Oxford) for valuable technical assistance in cell culture. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking (IMIJU) under grant agreement n_115439 , resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme ( FP7/2007-2013 ) and EFPIA companies’ in kind contribution. This publication reflects only the author’s 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. Funding to pay the Open Access publication charges for this article was provided by Parkinson's UK (COAF) ( J-1403 ) and Wellcome Trust ( 092762/Z/10/Z ).
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
