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Single-cell sequencing of iPSC-Dopamine neurons reconstructs disease progression and identifies HDAC4 as a regulator of Parkinson cell phenotypes

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 and Wade-Martins, Richard 2019. Single-cell sequencing of iPSC-Dopamine neurons reconstructs disease progression and identifies HDAC4 as a regulator of Parkinson cell phenotypes. Cell Stem Cell 24 (1) , pp. 93-106. 10.1016/j.stem.2018.10.023

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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
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Elsevier (Cell Press)
ISSN: 1934-5909
Date of First Compliant Deposit: 21 June 2019
Date of Acceptance: 23 October 2018
Last Modified: 14 Jul 2020 13:45
URI: http://orca-mwe.cf.ac.uk/id/eprint/123601

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