title: Genomic Analysis Reveals Disruption of Striatal Neuronal Development and Therapeutic Targets in Human Huntington's Disease Neural Stem Cells.
abstract: 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.
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Ring
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Mahru C
authors.initials: MC
authors.lastname: An
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Ningzhe
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: O'Brien
authors.affiliation: Departments of Neurology and Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Eliana Marisa
authors.initials: EM
authors.lastname: Ramos
authors.affiliation: Departments of Neurology and Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Fuying
authors.initials: F
authors.lastname: Gao
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Atwood
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Bailus
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Melov
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Mooney
authors.affiliation: Departments of Neurology and Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA. Electronic address: lellerby@buckinstitute.org.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ellerby
mesh_terms: D002460:Cell Line; D053263:Gene Regulatory Networks; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D009414:Nerve Growth Factors / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D000075388:Netrin-1; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D055495:Neurogenesis; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1