Regulation of Αlpha-Synuclein Gene (SNCA) by Epigenetic Modifier TET1 in Parkinson Disease

Subhrangshu Guhathakurta; Min Kyung Song; Sambuddha Basu; Goun Je; Ana Clara Cristovao; Yoon-Seong Kim

doi:10.5213/inj.2222206.103

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저자정보: Subhrangshu Guhathakurta (Division of Neurosciences Burnett School of Biomedical Science University of Central Florida) Min Kyung Song (Division of Neurosciences Burnett School of Biomedical Science University of Central Florida) Sambuddha Basu (Division of Neurosciences Burnett School of Biomedical Science University of Central Florida) Goun Je (Division of Neurosciences Burnett School of Biomedical Science University of Central Florida) Ana Clara Cristovao (Division of Neurosciences Burnett School of Biomedical Science University of Central Florida) Yoon-Seong Kim (Division of Neurosciences Burnett School of Biomedical Science University of Central Florida)

저널정보: 대한배뇨장애요실금학회 International Neurourology Journal International Neurourology Journal 제26권

발행연도: 2022.11

수록면: 85 - 93 (9page)

DOI: 10.5213/inj.2222206.103

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Purpose: Deregulation of SNCA encoding α-synuclein (α-SYN) has been associated with both the familial and sporadic forms of Parkinson disease (PD). Epigenetic regulation plays a crucial role in PD. The intron1 of SNCA harbors a large unmethylated CpG island. Ten-eleven translocation methylcytosine dioxygenase 1 (TET1), a CpG island binding protein, can repress gene expression by occupying hypomethylated CpG-rich promoters, and therefore SNCA could be a target for TET1. We investi gated whether TET1 binds to SNCA-intron1 and regulates gene expression. Methods: The dopaminergic neuronal cell line, ReNcell VM, was used. Reverse transcription-polymerase chain reaction (RT PCR), real time-quantitative PCR, Western blot, dot-blot, and Chromatin immunoprecipitation were conducted. The substan tia nigra tissues of postmortem PD samples were used to confirm the level of TET1 expression. Results: In the human dopaminergic cell line, ReNcell VM, overexpression of the DNA-binding domain of TET1 (TET1- CXXC) led to significant repression of α-SYN. On the contrary, knocking down of TET1 led to significantly higher expression of α-SYN. However, overexpression of the DNA-hydroxymethylating catalytic domain of TET1 failed to change the expression of α-SYN. Altogether, we showed that TET1 is a repressor for SNCA, and a CXXC domain of TET1 is the primary mediator for this repressive action independent of its hydroxymethylation activity. TET1 levels in PD patients are significantly lower than that in the controls. Conclusions: We identified that TET1 acts as a repressor for SNCA by binding the intron1 regions of the gene. As a high level of α-SYN is strongly implicated in the pathogenesis of PD, discovering a repressor for the gene encoding α-SYN is highly im portant for developing novel therapeutic strategies for the disease.

#Αlpha-synuclein #TET1 #Repressor #Parkinson disease

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