THAP1 regulates alpha-synuclein expression: Functional link of Dystonia with Parkinson’s disease pathways

• Applicant: Professor Dr. Olaf Riess
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 427402073

Mutations in THAP1 (thanatos-associated protein domain-containing apoptosis-associated protein 1) are responsible for primary dystonia 6 (DYT6). THAP1 as an transcription factor has numerous targets in neurons, however, the mechanism via THAP1 regulates their expression are largely unknown. In our preliminary studies, we observed that THAP1 regulates the expression of SNCA, a key protein in Parkinson’s disease (PD), in a cell type-dependent behaviour. Interestingly, THAP1 interacts with other key factors which bind to a strong enhancer region in intron 4 of alpha-synuclein. We already have identified several of these binding partners, but are going to decipher the entire binding complex. THAP1, in contrast, does not bind to this region directly. To investigate the cell-type specific expression based on the enhancer element in vivo, we will delete this region in a humanized alpha-synuclein overexpressing rat. Also, genetically, this enhancer region in SNCA harbors 3 DNA variants which are strongly associated with sporadic PD. We will thus integrate this risk haplotype and analyze whether SNCA expression is upregulated in these models. We will also investigate in vivo, if slight overexpression of human THAP1 is a risk factor to upregulate SNCA by crossing these two rat models. Through this project, we will characterize the transcriptional function of THAP1 and its role in two different neurological diseases, which will help us to understand common pathways linking primary dystonia and PD.

• DFG Programme: Research Grants