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

Autor:	Ring KL; Buck Institute for Research on Aging, Novato, CA 94945, USA., An MC; Buck Institute for Research on Aging, Novato, CA 94945, USA., Zhang N; Buck Institute for Research on Aging, Novato, CA 94945, USA., O'Brien RN; Buck Institute for Research on Aging, Novato, CA 94945, USA., Ramos EM; 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., Gao F; 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., Atwood R; Buck Institute for Research on Aging, Novato, CA 94945, USA., Bailus BJ; Buck Institute for Research on Aging, Novato, CA 94945, USA., Melov S; Buck Institute for Research on Aging, Novato, CA 94945, USA., Mooney SD; Buck Institute for Research on Aging, Novato, CA 94945, USA., Coppola G; 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., Ellerby LM; Buck Institute for Research on Aging, Novato, CA 94945, USA. Electronic address: lellerby@buckinstitute.org.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2015 Dec 08; Vol. 5 (6), pp. 1023-1038.
DOI:	10.1016/j.stemcr.2015.11.005
Abstrakt:	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. (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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