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

Fubo Cheng, Wenxu Zheng, Peter Antony Barbuti, Paola Bonsi, Change Liu, Nicolas Casadei, Giulia Ponterio, Maria Meringolo, Jakob Admard, Claire Marie Dording, Libo Yu-Taeger, Huu Phuc Nguyen, Kathrin Grundmann-Hauser, Thomas Ott, Henry Houlden, Antonio Pisani, Rejko Krüger, Olaf Riess

Research output: Contribution to journalArticleResearchpeer-review


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.

Original languageEnglish
Publication statusE-pub ahead of print - 7 Jan 2022


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