Dataset Information

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

ABSTRACT:

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 investigated 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 substantia 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.

Conclusion

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 important for developing novel therapeutic strategies for the disease.

SUBMITTER: Guhathakurta S

PROVIDER: S-EPMC9767688 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Guhathakurta Subhrangshu S Song Min Kyung MK Basu Sambuddha S Je Goun G Cristovao Ana Clara AC Kim Yoon-Seong YS

International neurourology journal 20221130 Suppl 2

<h4>Purpose</h4>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 investigated whe ...[more]

PMID: 36503211

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Project description:Olfactory dysfunction, one of the earliest non-motor symptoms of Parkinson disease (PD), is accompanied by abnormal deposition of SNCA/α-synuclein in the olfactory bulb (OB). The macroautophagy/autophagy-lysosome pathway (ALP) plays an important role in degrading pathological SNCA and modulating this pathway may be a promising treatment strategy. P2RX4 (purinergic receptor P2X, ligand-gated ion channel 4), a member of the purinergic receptor X family, is a key molecule regulating ALP. Piperine (PIP) is a Chinese medicine with anti-inflammatory and anti-oxidant effects. The present study investigated the neuroprotective effects of PIP on SNCA overexpression-induced PD cell and mouse models. We found that PIP oral administration (25, 50 and 100 mg/kg) for 6 weeks attenuated olfactory deficits and delayed motor deficits in Thy 1-SNCA transgenic mice overexpressing human SNCA. This was accompanied by a degradation of pathological SNCA in OB. In addition, PIP improved cell viability and promoted degradation of human SNCA in SK-N-SH cells. These protective effects were exerted via autophagy flux promotion by enhancing autophagosome-lysosome membrane fusion. Furthermore, tandem mass tag proteomics analyses showed that P2RX4 plays an important role in PIP treatment-induced activation of autophagy flux. These findings demonstrate that PIP exerts neuroprotective effects in PD models via promotion of autophagy flux and may be an effective agent for PD treatment.Abbreviations: 6-OHDA, 6-hydroxydopamine; ALP, autophagy-lysosome pathway; BafA1, bafilomycin A1; CoQ10, coenzyme Q10; DMSO: dimethyl sulfoxide; HPLC, high-performance liquid chromatography; IVE, ivermectin; LDH, lactate dehydrogenase; MAP1LC3/LC3-II, lipid-conjugated microtubule-associated protein 1 light chain 3; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; mRFP-GFP, tandem monomeric red fluorescent protein-green fluorescent protein; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; OB, olfactory bulb; P2RX4, purinergic receptor P2X, ligand-gated ion channel 4; PD, Parkinson disease; PBS: phosphate-buffered saline; PI: propidium iodide; PIP, piperine; PLG, piperlongumine; p-SNCA, SNCA phosphorylated at Ser129; Rap, rapamycin; RT-PCR: quantitative real-time PCR; SNARE, soluble N-ethylmaleimide-sensitive factor-attachment protein receptor; SNCA/α-synuclein, synuclein, alpha; STX17, syntaxin17; TG, transgenic; TH, tyrosine hydroxylase; UPS, ubiquitin-proteasome system; WT, wild-type.

Project description:ImportanceCognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature.ObjectiveTo determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD.Design, setting, and participantsWe studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE ε2/ε3/ε4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene.Main outcomes and measuresNine variables derived from 7 psychometric tests.ResultsThe APOE ε4 allele was associated with lower performance on the HVLT-R Total Recall (P = 6.7 × 10(-6); corrected P [Pc] = 6.0 × 10(-5)), Delayed Recall (P = .001; Pc = .009), and Recognition Discrimination Index (P = .004; Pc = .04); a semantic verbal fluency test (P = .002; Pc = .02); the Letter-Number Sequencing Test (P = 1 × 10(-5); Pc = 9 × 10(-5)); and Trail Making Test B minus Trail Making Test A (P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE ε4 allele was associated with lower scores on the HVLT-R Total Recall (P = .005; Pc = .045) and the semantic verbal fluency (P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests.Conclusions and relevanceOur data indicate that the APOE ε4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

Similar Datasets

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