Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Department of Neurology, The First Hospital of Jilin University, Changchun, China.
Brain. 2022 Nov 21;145(11):3968-3984. doi: 10.1093/brain/awac001.
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.
DYT6 肌张力障碍是由转录因子 THAP1 的突变引起的。THAP1 敲除或敲入小鼠模型揭示了复杂的基因表达变化，这些变化可能是导致 DYT6 肌张力障碍的发病机制。然而，THAP1 突变如何导致这些基因表达改变，以及这些基因表达变化是否也反映在 THAP1 患者的大脑中，目前尚不清楚。在这项研究中，我们使用表观遗传学和转录组学方法，结合多种模型系统[THAP1 患者的额皮质、THAP1 患者诱导多能干细胞（iPSC）衍生的中脑多巴胺能神经元、THAP1 杂合敲除大鼠模型和 THAP1 杂合敲除 SH-SY5Y 细胞系]，揭示了 THAP1 的新功能和 DYT6 肌张力障碍的潜在发病机制。我们观察到，THAP1 仅靶向其突变引起的少数差异表达基因。THAP1 突变主要通过调节 SP1 家族成员、SP1 和 SP4，以细胞类型依赖的方式导致基因失调。比较 THAP1 患者的 iPSC 衍生的中脑多巴胺能神经元和 THAP1 杂合敲除大鼠纹状体中检测到的全局差异表达基因，我们观察到许多共同失调的基因，其中 61 个基因参与与肌张力障碍综合征相关的途径，如突触传递、神经系统发育和运动行为。进一步的行为和电生理研究证实了这些途径在 THAP1 敲除大鼠中的参与。总之，我们的研究描述了 THAP1 的功能，并有助于理解人类和大鼠原发性肌张力障碍的发病机制。由于 SP1 家族成员在一些神经退行性疾病中失调，我们的数据可能将 THAP1 肌张力障碍与多种神经疾病联系起来，从而提供共同的治疗靶点。
