Publication
Title
Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice
Author
Institution/Organisation
HD iPSC Consortium
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.
Language
English
Source (journal)
Nature neuroscience. - London
Publication
London : 2017
ISSN
1097-6256 [Print]
1546-1726 [Online]
Volume/pages
20 :5 (2017) , p. 648-660
ISI
000400004300006
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Publication type
Subject
External links
Web of Science
Record
Identification
Creation 10.10.2018
Last edited 16.09.2021