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Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice

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; Winokur, Sara T; Casale, Malcolm S; Thompson, Leslie M; Pardo, Mónica; Díaz-Barriga, A Gerardo García; Straccia, Marco; Sanders, Phil; Alberch, Jordi; Canals, Josep M; Kaye, Julia A; Dunlap, Mariah; Jo, Lisa; May, Hanna; Mount, Elliot; Anderson-Bergman, Cliff; Haston, Kelly; Finkbeiner, Steven; Allen, Nicholas D; Kemp, Paul J; Atwal, Ranjit Singh; Biagioli, Marta; Gusella, James F; MacDonald, Marcy E; Akimov, Sergey S; Arbez, Nicolas; Stewart, Jacqueline; Ross, Christopher A; Mattis, Virginia B; Tom, Colton M; Mattis, Virginia B; Tom, Colton M; Ornelas, Loren; Sahabian, Anais; Lenaeus, Lindsay; Mandefro, Berhan; Sareen, Dhruv; Svendsen, Clive N; Kedaigle, Amanda Joy; Wasylenko, Theresa Anne; Yildirim, Ferah; Ng, Christopher W.; Milani, Pamela; Housman, David E; Fraenkel, Ernest; ... Show more Show less
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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.
Date issued
2017-03
URI
http://hdl.handle.net/1721.1/116515
Department
Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MIT
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
ISSN
1097-6256
1546-1726

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