Intronic enhancers of the human SNCA gene predominantly regulate its expression in brain in vivo

Evidence from patients with Parkinson's disease (PD) and our previously reported a-synuclein (SNCA) transgenic rat model support the idea that increased SNCA protein is a substantial risk factor of PD pathogenesis. However, little is known about the transcription control of the human SNCA gene in the brain in vivo. Here, we identified that the DYT6 gene product THAP1 (THAP domain-containing apoptosis-associated protein 1) and its interaction partner CTCF (CCCTC-binding factor) act as transcription regulators of SNCA. THAP1 controls SNCA intronic enhancers' activities, while CTCF regulates its enhancer-promoter loop formation. The SNCA intronic enhancers present neurodevelopment- dependent activities and form enhancer clusters similar to super-enhancers in the brain, in which the PD-associated single-nucleotide polymorphisms are enriched. Deletion of the SNCA intronic enhancer clusters prevents the release of paused RNA polymerase II from its promoter and subsequently reduces its expression drastically in the brain, which may provide new therapeutic approaches to prevent its accumulation and thus related neurodegenerative diseases defined as synucleinopathies.

Automated summary

Evidence suggests that increased SNCA protein is a significant risk factor for Parkinson's disease (PD). This study identifies THAP1 and CTCF as transcription regulators of SNCA in the brain. SNCA intronic enhancers show neurodevelopment-dependent activities and form enhancer clusters enriched with PD-associated single-nucleotide polymorphisms. Deletion of these enhancer clusters reduces SNCA expression in the brain by preventing the release of paused RNA polymerase II from its promoter.