Reference : DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family.
Scientific journals : Article
Human health sciences : Neurology
Systems Biomedicine
DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family.
Cheng, Fubo [> >]
Zheng, Wenxu [> >]
Barbuti, Peter Antony [> >]
Bonsi, Paola [> >]
Liu, Chang [> >]
Casadei, Nicolas [> >]
Ponterio, Giulia [> >]
Meringolo, Maria [> >]
Admard, Jakob [> >]
Dording, Claire Marie [> >]
Yu-Taeger, Libo [> >]
Nguyen, Huu Phuc [> >]
Grundmann-Hauser, Kathrin [> >]
Ott, Thomas [> >]
Houlden, Henry [> >]
Pisani, Antonio [> >]
Krüger, Rejko mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
Riess, Olaf [> >]
Brain : a journal of neurology
[en] Humans ; Mice ; Animals ; Rats ; Dystonia/genetics ; Nuclear Proteins/genetics ; DNA-Binding Proteins/metabolism ; Apoptosis Regulatory Proteins/genetics ; Neuroblastoma ; Dystonic Disorders/genetics ; Mutation/genetics ; Sp1 Transcription Factor/genetics ; SP1 family ; THAP1 dystonia ; epigenetics ; primary dystonia ; therapeutic targets
[en] DYT6 dystonia is caused by mutations in the transcription factor THAP1. THAP1 knock-out or knock-in mouse models revealed complex gene expression changes, which are potentially responsible for the pathogenesis of DYT6 dystonia. However, how THAP1 mutations lead to these gene expression alterations and whether the gene expression changes are also reflected in the brain of THAP1 patients are still unclear. In this study we used epigenetic and transcriptomic approaches combined with multiple model systems [THAP1 patients' frontal cortex, THAP1 patients' induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons, THAP1 heterozygous knock-out rat model, and THAP1 heterozygous knock-out SH-SY5Y cell lines] to uncover a novel function of THAP1 and the potential pathogenesis of DYT6 dystonia. We observed that THAP1 targeted only a minority of differentially expressed genes caused by its mutation. THAP1 mutations lead to dysregulation of genes mainly through regulation of SP1 family members, SP1 and SP4, in a cell type dependent manner. Comparing global differentially expressed genes detected in THAP1 patients' iPSC-derived midbrain dopaminergic neurons and THAP1 heterozygous knock-out rat striatum, we observed many common dysregulated genes and 61 of them were involved in dystonic syndrome-related pathways, like synaptic transmission, nervous system development, and locomotor behaviour. Further behavioural and electrophysiological studies confirmed the involvement of these pathways in THAP1 knock-out rats. Taken together, our study characterized the function of THAP1 and contributes to the understanding of the pathogenesis of primary dystonia in humans and rats. As SP1 family members were dysregulated in some neurodegenerative diseases, our data may link THAP1 dystonia to multiple neurological diseases and may thus provide common treatment targets.
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail:

File(s) associated to this reference

Fulltext file(s):

Limited access
Fubo Brain DYT6.pdfAuthor preprint2.64 MBRequest a copy

Bookmark and Share SFX Query

All documents in ORBilu are protected by a user license.