UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family

Cheng, F; Zheng, W; Barbuti, PA; Bonsi, P; Liu, C; Casadei, N; Ponterio, G; ... Riess, O; + view all (2022) DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family. Brain , 145 (11) pp. 3968-3984. 10.1093/brain/awac001. Green open access

[thumbnail of awac001.pdf]
Preview
Text
awac001.pdf - Accepted Version

Download (2MB) | Preview

Abstract

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' iPSCs 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' iPSCs derived midbrain dopaminergic neurons and THAP1 heterozygous knock-out rat striatum, we observed many common dysregulated genes and 61 of them are involved in dystonic syndromes related pathways, like synaptic transmission, nervous system development, and locomotor behavior. Further behavioral and electrophysiological studies confirmed the involvement of these pathways in THAP1 knock-out rats. Taking together, our study characterized the function of THAP1 and contributes to the understanding of the pathogenesis of primary dystonia in human and rat. As SP1 family members are dysregulated in some neurodegenerative diseases, our data may link THAP1 dystonia to multiple neurological diseases and may thus provide common treatment targets.

Type: Article
Title: DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/brain/awac001
Publisher version: https://doi.org/10.1093/brain/awac001
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: SP1 family, THAP1 dystonia, epigenetics, primary dystonia, therapeutic targets
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10142136
Downloads since deposit
131Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item