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

THAP1 调节 α-突触核蛋白表达：肌张力障碍与帕金森病通路的功能联系

• 批准号: 427402073
• 负责人: Professor Dr. Olaf Riess
• 金额: --
• 依托单位: Abteilung für Medizinische Genetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/427402073?language=en
• 关键词: THAP1; regulates; alpha; synuclein; expression

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.

THAP 1（含死亡相关蛋白结构域的死亡相关蛋白1）的突变导致原发性肌张力障碍6（DYT 6）。THAP 1作为一种转录因子，在神经元中有许多靶点，然而，通过THAP 1调节其表达的机制在很大程度上是未知的。在我们的初步研究中，我们观察到THAP 1调节SNCA的表达，SNCA是帕金森病（PD）的关键蛋白，具有细胞类型依赖性。有趣的是，THAP 1与其他关键因子相互作用，这些因子与α-突触核蛋白内含子4中的强增强子区域结合。我们已经鉴定了其中几种结合伴侣，但我们将破译整个结合复合物。相反，THAP 1不直接与该区域结合。为了研究基于增强子元件的体内细胞类型特异性表达，我们将在人源化α-突触核蛋白过表达大鼠中删除该区域。此外，从遗传学上讲，SNCA中的该增强子区域含有3种与散发性PD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表达是否在这些模型中上调。我们还将通过交叉这两种大鼠模型在体内研究人类THAP 1的轻微过表达是否是上调SNCA的风险因素。通过这个项目，我们将描述THAP 1的转录功能及其在两种不同神经系统疾病中的作用，这将有助于我们了解原发性肌张力障碍和PD之间的共同途径。