Genomic Analysis Reveals Disruption of Striatal Neuronal Development and Therapeutic Targets in Human Huntington’s Disease Neural Stem Cells

Summary

We utilized induced pluripotent stem cells (iPSCs) derived from Huntington’s disease (HD) patients as a human model of HD and determined that the disease phenotypes only manifest in the differentiated neural stem cell (NSC) stage, not in iPSCs. To understand the molecular basis for the CAG repeat expansion-dependent disease phenotypes in NSCs, we performed transcriptomic analysis of HD iPSCs and HD NSCs compared to isogenic controls. Differential gene expression and pathway analysis pointed to transforming growth factor β (TGF-β) and netrin-1 as the top dysregulated pathways. Using data-driven gene coexpression network analysis, we identified seven distinct coexpression modules and focused on two that were correlated with changes in gene expression due to the CAG expansion. Our HD NSC model revealed the dysregulation of genes involved in neuronal development and the formation of the dorsal striatum. The striatal and neuronal networks disrupted could be modulated to correct HD phenotypes and provide therapeutic targets.

Graphical Abstract

Highlights

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  HD stem cell models have phenotypes in the differentiated NSC and not the IPSC state

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  Bioinformatic analysis of RNA-seq data identifies TGF-β and netrin-1 in HD phenotypes

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  WGCNA analysis in the HD-NSC linked module to development of the dorsal striatum

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  Modulation of TGF-β and netrin-1 in HD-NSCs is neuroprotective

Abstract

Ellerby and colleagues use expression profiling and bioinformatic analysis to identify critical pathways mediating Huntington’s disease (HD) phenotypes in neural stem cells. They identify and show modulation of TFG-β and netrin-1 signaling is relevant to HD phenotypes found in neural stem cells and not iPSCs. Further, HD phenotypes are linked to genes in the dorsal striatum.