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

• DOI: 10.1016/j.stemcr.2015.11.005
• Publication Date: 2015-12-08T18:28:09Z
• Authors: Karen L. Ring; Mahru C. An; Ningzhe Zhang; Robert N. O’Brien; Eliana Marisa Ramos; Fuying Gao; Robert Atwood; Barbara J. Bailus; Simon Melov; Sean D. Mooney; Giovanni Coppola; Lisa M. Ellerby
• Keywords: Huntington's Disease; Medicine (General); QH301-705.5; Neurogenesis; Clinical Sciences; Induced Pluripotent Stem Cells; Nerve Tissue Proteins; Neurodegenerative; Regenerative Medicine; Article; Cell Line; 03 medical and health sciences; Rare Diseases; R5-920; Neural Stem Cells; Stem Cell Research - Nonembryonic - Human; Transforming Growth Factor beta; Genetics; 2.1 Biological and endogenous factors; Humans; Gene Regulatory Networks; Nerve Growth Factors; Aetiology; Biology (General); Huntingtin Protein; 0303 health sciences; Tumor Suppressor Proteins; Human Genome; Neurosciences; Netrin-1; Stem Cell Research; Brain Disorders; 3. Good health; Huntington Disease; Neurological; Mutation; Stem Cell Research - Nonembryonic - Non-Human; Biochemistry and Cell Biology; Transcriptome; Biotechnology

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.