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Publication

Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes.

Cell stem cell | 2019

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.

Pubmed ID: 30503143 RIS Download

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Associated grants

Agency: Medical Research Council, United Kingdom
Id: MR/M00919X/1
Agency: Medical Research Council, United Kingdom
Id: G84/6443
Agency: Medical Research Council, United Kingdom
Id: MC_UP_A320_1004
Agency: Medical Research Council, United Kingdom
Id: MC_UU_00016/15
Agency: Department of Health, United Kingdom
Agency: Medical Research Council, United Kingdom
Id: MC_UU_12009/16
Agency: Medical Research Council, United Kingdom
Id: MC_PC_16034
Agency: Wellcome Trust, United Kingdom
Id: 090532/Z/09/Z
Agency: Medical Research Council, United Kingdom
Id: MC_EX_MR/N50192X/1
Agency: Medical Research Council, United Kingdom
Id: MR/M024962/1
Agency: Medical Research Council, United Kingdom
Id: MR/L023784/1
Agency: Medical Research Council, United Kingdom
Id: MR/L006340/1
Agency: Wellcome Trust, United Kingdom
Id: WTISSF121302
Agency: Parkinson's UK, United Kingdom
Id: J-0901
Agency: Medical Research Council, United Kingdom
Id: MC_UU_12021/4
Agency: Medical Research Council, United Kingdom
Id: MR/L023784/2

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