Lang, Charmaine, Campbell, Kieran R., Ryan, Brent J., Carling, Phillippa, Attar, Moustafa, Vowles, Jane, Perestenko, Olga V., Bowden, Rory, Baig, Fahd, Kasten, Meike, Hu, Michele T., Cowley, Sally A., Webber, Caleb ![]() ![]() |
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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.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) |
Additional Information: | This article is licensed under a Creative Commons Attribution 4.0 International License. |
Publisher: | Elsevier |
ISSN: | 1934-5909 |
Date of First Compliant Deposit: | 21 June 2019 |
Date of Acceptance: | 23 October 2018 |
Last Modified: | 04 May 2023 09:24 |
URI: | https://orca.cardiff.ac.uk/id/eprint/123601 |
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