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.
Cell Stem Cell
93 - 106.e6
Parkinson’s disease, histone deacetylase 4, induced pluripotent stem cells, single-cell RNA sequencing, Disease Progression, Dopamine, Dopaminergic Neurons, Endoplasmic Reticulum Stress, Gene Expression Profiling, Gene Expression Regulation, Glucosylceramidase, Histone Deacetylases, Humans, Induced Pluripotent Stem Cells, Mutation, Parkinson Disease, Phenotype, Repressor Proteins, Single-Cell Analysis, Transcriptome