Article (Scientific journals)
DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family.
Cheng, Fubo; Zheng, Wenxu; Barbuti, Peter Antony et al.
2022In Brain: a Journal of Neurology, 145 (11), p. 3968-3984
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Keywords :
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
Abstract :
[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.
Disciplines :
Neurology
Author, co-author :
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 ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Riess, Olaf
More authors (8 more) Less
External co-authors :
yes
Language :
English
Title :
DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family.
Publication date :
07 January 2022
Journal title :
Brain: a Journal of Neurology
ISSN :
1460-2156
Publisher :
Oxford University Press, Oxford, United Kingdom
Volume :
145
Issue :
11
Pages :
3968-3984
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Commentary :
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Available on ORBilu :
since 20 January 2023

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