Journal
CELL STEM CELL
Volume 24, Issue 1, Pages 93-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2018.10.023
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Funding
- Monument Trust Discovery Award from Parkinson's UK
- Medical Research Council, UK
- Oxford Martin School [LC0910-004]
- Wellcome Trust [092762/Z/10/Z, 090532/Z/09/Z, WTISSF121302]
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust
- University of Oxford
- Dementia and Neurodegenerative Diseases Research Network (DeNDRoN)
- Innovative Medicines Initiative Joint Undertaking (IMIJU) from the European Union [n_115439]
- Parkinson's UK (COAF) [J-1403]
- Wellcome Trust [092762/Z/10/Z] Funding Source: Wellcome Trust
- MRC [MC_UP_A320_1004, MR/L023784/2, UKDRI-3005, MC_EX_MR/N50192X/1, MR/M00919X/1, MR/L023784/1, MR/L006340/1, G84/6443, MC_UU_12021/4, MC_UU_12009/16, MC_PC_16034, MR/M024962/1] Funding Source: UKRI
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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.
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