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

Ryan G. Lim, Lisa L. Salazar, Daniel K. Wilton, Alvin R. King, Jennifer T. Stocksdale, Delaram Sharifabad, Alice L. Lau, Beth Stevens, Jack C. Reidling, Sara T. Winokur, Malcolm S. Casale, Leslie M. Thompson, Mónica Pardo, A. Gerardo García Díaz-Barriga, Marco Straccia, Phil Sanders, Jordi Alberch, Josep M. Canals, Julia A. Kaye, Mariah Dunlap & 31 others Lisa Jo, Hanna May, Elliot Mount, Cliff Anderson-Bergman, Kelly Haston, Steven Finkbeiner, Amanda J. Kedaigle, Theresa A. Gipson, Ferah Yildirim, Christopher W. Ng, Pamela Milani, David E. Housman, Ernest Fraenkel, Nicholas D. Allen, Paul J. Kemp, Ranjit Singh Atwal, Marta Biagioli, James F. Gusella, Marcy E. MacDonald, Sergey S. Akimov, Nicolas Arbez, Jacqueline Stewart, Christopher A. Ross, Virginia B. Mattis, Colton M. Tom, Loren Ornelas, Anais Sahabian, Lindsay Lenaeus, Berhan Mandefro, Dhruv Sareen, The HD iPSC Consortium

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
Pages648-660
Number of pages13
JournalNature Neuroscience
Volume20
Issue number5
DOIs
StatePublished - May 1 2017

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Huntington Disease
Pharmacology
Histone Code
Genes
Isoxazoles
Corpus Striatum
Induced Pluripotent Stem Cells
Epigenomics
gamma-Aminobutyric Acid
Glutamic Acid
Homeostasis
RNA
Pathology
Calcium
Phenotype
Gene Expression
polyglutamine
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Lim, R. G., Salazar, L. L., Wilton, D. K., King, A. R., Stocksdale, J. T., Sharifabad, D., ... The HD iPSC Consortium (2017). Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice. Nature Neuroscience, 20(5), 648-660. DOI: 10.1038/nn.4532

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; The HD iPSC Consortium.

In: Nature Neuroscience, Vol. 20, No. 5, 01.05.2017, p. 648-660.

Research output: Contribution to journalArticle

Lim, RG, Salazar, LL, Wilton, DK, King, AR, Stocksdale, JT, Sharifabad, D, Lau, AL, Stevens, B, Reidling, JC, Winokur, ST, Casale, MS, Thompson, LM, Pardo, M, Díaz-Barriga, AGG, Straccia, M, Sanders, P, Alberch, J, Canals, JM, Kaye, JA, Dunlap, M, Jo, L, May, H, Mount, E, Anderson-Bergman, C, Haston, K, Finkbeiner, S, Kedaigle, AJ, Gipson, TA, Yildirim, F, Ng, CW, Milani, P, Housman, DE, Fraenkel, E, Allen, ND, Kemp, PJ, Atwal, RS, Biagioli, M, Gusella, JF, MacDonald, ME, Akimov, SS, Arbez, N, Stewart, J, Ross, CA, Mattis, VB, Tom, CM, Ornelas, L, Sahabian, A, Lenaeus, L, Mandefro, B, Sareen, D & The HD iPSC Consortium 2017, 'Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice' Nature Neuroscience, vol. 20, no. 5, pp. 648-660. DOI: 10.1038/nn.4532
Lim RG, Salazar LL, Wilton DK, King AR, Stocksdale JT, Sharifabad D et al. Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice. Nature Neuroscience. 2017 May 1;20(5):648-660. Available from, DOI: 10.1038/nn.4532
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 ; The HD iPSC Consortium. / Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice. In: Nature Neuroscience. 2017 ; Vol. 20, No. 5. pp. 648-660
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