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

原发性肌张力障碍6(DYT6)与THAP1(乙醇相关蛋白结构域含凋亡相关蛋白1)基因突变有关。THAP1作为一种转录因子，在神经元中有许多靶点，然而，THAP1调控其表达的机制尚不清楚。在我们的初步研究中，我们观察到THAP1在细胞类型依赖的行为中调节SNCA的表达，SNCA是帕金森病(PD)的关键蛋白。有趣的是，THAP1与其他关键因子相互作用，这些关键因子结合到α-突触核蛋白内含子4的一个强大的增强子区域。我们已经确定了这些结合伙伴中的几个，但将破译整个结合复合体。相反，THAP1不直接与这个区域结合。为了研究体内基于增强子元件的细胞类型特异性表达，我们将在人源化的α-突触核蛋白过度表达的大鼠中删除这一区域。此外，从基因上讲，SNCA的这个增强子区域包含3个与散发性帕金森病密切相关的DNA变体。因此，我们将整合这种风险单倍型，并分析SNCA的表达是否在这些模型中上调。我们还将在体内研究，如果人THAP1轻微过度表达是通过交叉这两个大鼠模型上调SNCA的危险因素。通过这个项目，我们将表征THAP1的转录功能及其在两种不同的神经系统疾病中的作用，这将有助于我们了解连接原发性肌张力障碍和帕金森病的共同途径。

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.