Role of the Dystonia type 6 gene product THAP1 in gene regulation and in neurological diseases

• Applicant: Fubo Cheng, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Human Genetics
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505858170

Mutations in THAP1 (thanatos-associated protein domain-containing apoptosis-associated protein 1) are responsible for primary dystonia 6 (DYT6). Recent reports of gene mutations indicate that DYT6 dystonia is the second most common pure primary monogenic dystonia next to DYT1 dystonia. Our previous study using epigenetic and transcriptomic approaches combined with multiple model systems identified that THAP1 plays cell-type dependent function in regulating gene expression, but how THAP1 regulates gene expression in neuronal cells and the pathogenesis of DYT6 dystonia are still unclear so far. In this project, we will utilize the proteomics, transcriptomics, epigenetics, and chromatin conformation capture analysis to first isolate the THAP1 interaction partners in neuronal cells and then to characterize the role of THAP1 in regulating gene expression. As striatum is the key node responsible for primary dystonia, further single-nuclear RNA-seq of THAP1+/- rat striatum tissues will be performed to analysis gene expression changes at single neuron level. Through this study, we will not only characterize how THAP1 regulates gene expression, but will also find out the pathogenesis of DYT6 dystonia, which may help us to find out new treatment targets for this neurological disease.

• DFG Programme: Research Grants