Please use this identifier to cite or link to this item:
Title: Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells
Authors: Lopes, Carla 
Aubert, Sophie 
Bourgois-Rocha, Fany 
Barnat, Monia 
Rego, Ana Cristina 
Déglon, Nicole 
Perrier, Anselme L. 
Humbert, Sandrine 
Keywords: Adult; Age of Onset; Alleles; Antigens, Nuclear; Cells, Cultured; Dynactin Complex; Dyneins; Genes, Dominant; Human Embryonic Stem Cells; Humans; Huntingtin Protein; Microtubule-Associated Proteins; Nerve Tissue Proteins; Neural Stem Cells; Nuclear Matrix-Associated Proteins; Peptides; Pluripotent Stem Cells; Polymorphism, Single Nucleotide; Protein Transport; RNA Interference; RNA, Small Interfering; Spindle Apparatus; Subcellular Fractions; Trinucleotide Repeat Expansion; Mutation
Issue Date: 2016
Serial title, monograph or event: PLOS ONE
Volume: 11
Issue: 2
Abstract: Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington's disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions.
DOI: 10.1371/journal.pone.0148680
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais

Files in This Item:
File Description SizeFormat
Lopes et al., PLoS One-16.pdf3.78 MBAdobe PDFView/Open
Show full item record


checked on May 20, 2024

Citations 10

checked on May 2, 2024

Page view(s) 5

checked on May 21, 2024


checked on May 21, 2024

Google ScholarTM




Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.