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

Stem Cell Reports. 2015 Dec 8;5(6):1023-1038. doi: 10.1016/j.stemcr.2015.11.005.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line
  • Gene Regulatory Networks
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / pathology*
  • Huntington Disease / physiopathology
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology*
  • Mutation
  • Nerve Growth Factors / genetics
  • Nerve Tissue Proteins / genetics
  • Netrin-1
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology*
  • Neurogenesis
  • Transcriptome*
  • Transforming Growth Factor beta / genetics
  • Tumor Suppressor Proteins / genetics


  • HTT protein, human
  • Huntingtin Protein
  • NTN1 protein, human
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Transforming Growth Factor beta
  • Tumor Suppressor Proteins
  • Netrin-1