期刊
NATURE NEUROSCIENCE
卷 20, 期 5, 页码 648-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.4532
关键词
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资金
- NIH [NS078370, U54 NS091046, NS089076, P50NS16367, R01GM089903, NS101996-01, R01NS084298, T32GM008334]
- CHDI Foundation
- American Heart Association, CIRM fellowship
- American Heart Association, NRSA fellowship
- Hereditary Disease Foundation
- Taube-Koret Center
- Hellman Family Foundation
- UCI Institute for Clinical and Translational Science
- Huntington's Disease Society of America
- HD CARE
- Ministerio de Economia y Competitividad [SAF 2014-57160-R, SAF2015-66505-R]
- ISCIII-Subdireccion General de Evaluacion
- European Regional Development Fund (ERDF) (RETICS) [RD12/0019/0002]
- ACCIO (Catalonia Trade Investment
- Generalitat de Catalunya)
- European Community under the Catalonian ERDF operational program, Spain
- European Union
- Ser Cymru Life Sciences & Health Network in Drug Discovery Programme
- Cancer Center Support Grant at the University of California, Irvine [CA-62203]
- National Science Foundation [DB1-0821391]
- National Institutes of Health [P30-ES002109]
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.
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