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

Lim, Ryan G., Salazar, Lisa L., Wilton, Daniel K., King, Alvin R., Stocksdale, Jennifer T., Sharifabad, Delaram, Lau, Alice L., 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, Kedaigle, Amanda J., Gipson, Theresa A., Yildirim, Ferah, Ng, Christopher W., Milani, Pamela, Housman, David E., Fraenkel, Ernest, 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., Ornelas, Loren, Sahabian, Anais, Lenaeus, Lindsay, Mandefro, Berhan, Sareen, Dhruv and Svendsen, Clive N. 2017. Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice. Nature Neuroscience 20 (5) , pp. 648-660. 10.1038/nn.4532

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Additional Information: The HD iPSC Consortium
Publisher: Nature Publishing Group
ISSN: 1097-6256
Funders: CHDI
Date of First Compliant Deposit: 26 June 2017
Date of Acceptance: 23 February 2017
Last Modified: 09 Nov 2020 13:30

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