Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice
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nihms906334.pdf
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Author(s)
HD iPSC Consortium
Lim, Ryan G
Salazar, Lisa L
Wilton, Daniel K
King, Alvin R
Stocksdale, Jennifer T
Sharifabad, Delaram
Lau, L Alice
Stevens, Beth
Reidling, Jack C
Date Issued
March 2017
Journal
Nature Neuroscience
Publisher
Springer Nature
Citation
Lim, Ryan G et al. “Developmental Alterations in Huntington’s Disease Neural Cells and Pharmacological Rescue in Cells and Mice.” Nature Neuroscience 20, 5 (March 2017): 648–660 © 2017 Nature America, Inc., part of Springer Nature
Version
Author's final manuscript
Abstract
Neural cultures derived from Huntington's disease (HD) patient-derived induced pluripotent stem cells were used for 'omics' analyses to identify mechanisms underlying neurodegeneration. RNA-seq analysis identified genes in glutamate and GABA signaling, axonal guidance and calcium influx whose expression was decreased in HD cultures. One-third of gene changes were in pathways regulating neuronal development and maturation. When mapped to stages of mouse striatal development, the profiles aligned with earlier embryonic stages of neuronal differentiation. We observed a strong correlation between HD-related histone marks, gene expression and unique peak profiles associated with dysregulated genes, suggesting a coordinated epigenetic program. Treatment with isoxazole-9, which targets key dysregulated pathways, led to amelioration of expanded polyglutamine repeat-associated phenotypes in neural cells and of cognitive impairment and synaptic pathology in HD model R6/2 mice. These data suggest that mutant huntingtin impairs neurodevelopmental pathways that could disrupt synaptic homeostasis and increase vulnerability to the pathologic consequence of expanded polyglutamine repeats over time.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1038/NN.4532
