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| Home > Publications Database > The Alpha-Synuclein Gene (SNCA) is a Genomic Target of Methyl-CpG Binding Protein 2 (MeCP2)-Implications for Parkinson's Disease and Rett Syndrome. > print |
| Home > Publications Database > The Alpha-Synuclein Gene (SNCA) is a Genomic Target of Methyl-CpG Binding Protein 2 (MeCP2)-Implications for Parkinson's Disease and Rett Syndrome. > print |
| 001 | 272839 | ||
| 005 | 20241029085444.0 | ||
| 024 | 7 | _ | |a 10.1007/s12035-024-03974-3 |2 doi |
| 024 | 7 | _ | |a pmid:38429622 |2 pmid |
| 024 | 7 | _ | |a pmc:PMC11415397 |2 pmc |
| 024 | 7 | _ | |a 0893-7648 |2 ISSN |
| 024 | 7 | _ | |a 1559-1182 |2 ISSN |
| 024 | 7 | _ | |a altmetric:160301929 |2 altmetric |
| 037 | _ | _ | |a DZNE-2024-01257 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 570 |
| 100 | 1 | _ | |a Schmitt, Ina |0 P:(DE-2719)2810444 |b 0 |e First author |
| 245 | _ | _ | |a The Alpha-Synuclein Gene (SNCA) is a Genomic Target of Methyl-CpG Binding Protein 2 (MeCP2)-Implications for Parkinson's Disease and Rett Syndrome. |
| 260 | _ | _ | |a Totowa, NJ |c 2024 |b Humana Press |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1729589177_17582 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a Mounting evidence suggests a prominent role for alpha-synuclein (a-syn) in neuronal cell function. Alterations in the levels of cellular a-syn have been hypothesized to play a critical role in the development of Parkinson's disease (PD); however, mechanisms that control expression of the gene for a-syn (SNCA) in cis and trans as well as turnover of a-syn are not well understood. We analyzed whether methyl-CpG binding protein 2 (MeCP2), a protein that specifically binds methylated DNA, thus regulating transcription, binds at predicted binding sites in intron 1 of the SNCA gene and regulates a-syn protein expression. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility-shift assays (EMSA) were used to confirm binding of MeCP2 to regulatory regions of SNCA. Site-specific methylation and introduction of localized mutations by CRISPR/Cas9 were used to investigate the binding properties of MeCP2 in human SK-N-SH neuroblastoma cells. The significance of MeCP2 for SNCA regulation was further investigated by overexpressing MeCP2 and mutated variants of MeCP2 in MeCP2 knockout cells. We found that methylation-dependent binding of MeCP2 at a restricted region of intron 1 of SNCA had a significant impact on the production of a-syn. A single nucleotide substitution near to CpG1 strongly increased the binding of MeCP2 to intron 1 of SNCA and decreased a-syn protein expression by 60%. In contrast, deletion of a single nucleotide closed to CpG2 led to reduced binding of MeCP2 and significantly increased a-syn levels. In accordance, knockout of MeCP2 in SK-N-SH cells resulted in a significant increase in a-syn production, demonstrating that SNCA is a genomic target for MeCP2 regulation. In addition, the expression of two mutated MeCP2 variants found in Rett syndrome (RTT) showed a loss of their ability to reduce a-syn expression. This study demonstrates that methylation of CpGs and binding of MeCP2 to intron 1 of the SNCA gene plays an important role in the control of a-syn expression. In addition, the changes in SNCA regulation found by expression of MeCP2 variants carrying mutations found in RTT patients may be of importance for the elucidation of a new molecular pathway in RTT, a rare neurological disorder caused by mutations in MECP2. |
| 536 | _ | _ | |a 353 - Clinical and Health Care Research (POF4-353) |0 G:(DE-HGF)POF4-353 |c POF4-353 |f POF IV |x 0 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de |
| 650 | _ | 7 | |a SNCA |2 Other |
| 650 | _ | 7 | |a Alpha-synuclein |2 Other |
| 650 | _ | 7 | |a DNA methylation |2 Other |
| 650 | _ | 7 | |a Epigenetic |2 Other |
| 650 | _ | 7 | |a Genomic target |2 Other |
| 650 | _ | 7 | |a Intron |2 Other |
| 650 | _ | 7 | |a MeCP2 |2 Other |
| 650 | _ | 7 | |a Methyl-CpG binding protein 2 |2 Other |
| 650 | _ | 7 | |a Parkinson’s disease |2 Other |
| 650 | _ | 7 | |a RTT |2 Other |
| 650 | _ | 7 | |a Rett syndrome |2 Other |
| 650 | _ | 7 | |a Methyl-CpG-Binding Protein 2 |2 NLM Chemicals |
| 650 | _ | 7 | |a alpha-Synuclein |2 NLM Chemicals |
| 650 | _ | 7 | |a SNCA protein, human |2 NLM Chemicals |
| 650 | _ | 7 | |a MECP2 protein, human |2 NLM Chemicals |
| 650 | _ | 2 | |a Methyl-CpG-Binding Protein 2: genetics |2 MeSH |
| 650 | _ | 2 | |a Methyl-CpG-Binding Protein 2: metabolism |2 MeSH |
| 650 | _ | 2 | |a alpha-Synuclein: metabolism |2 MeSH |
| 650 | _ | 2 | |a alpha-Synuclein: genetics |2 MeSH |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a Rett Syndrome: genetics |2 MeSH |
| 650 | _ | 2 | |a Rett Syndrome: metabolism |2 MeSH |
| 650 | _ | 2 | |a Cell Line, Tumor |2 MeSH |
| 650 | _ | 2 | |a Parkinson Disease: genetics |2 MeSH |
| 650 | _ | 2 | |a Parkinson Disease: metabolism |2 MeSH |
| 650 | _ | 2 | |a DNA Methylation: genetics |2 MeSH |
| 650 | _ | 2 | |a Protein Binding |2 MeSH |
| 650 | _ | 2 | |a Introns: genetics |2 MeSH |
| 650 | _ | 2 | |a Mutation: genetics |2 MeSH |
| 700 | 1 | _ | |a Evert, Bernd O |0 0009-0002-3443-4096 |b 1 |
| 700 | 1 | _ | |a Sharma, Amit |0 0000-0002-2216-5389 |b 2 |
| 700 | 1 | _ | |a Khazneh, Hassan |b 3 |
| 700 | 1 | _ | |a Murgatroyd, Chris |0 0000-0002-6885-7794 |b 4 |
| 700 | 1 | _ | |a Wüllner, Ullrich |0 P:(DE-2719)2000056 |b 5 |e Last author |
| 773 | _ | _ | |a 10.1007/s12035-024-03974-3 |g Vol. 61, no. 10, p. 7830 - 7844 |0 PERI:(DE-600)2079384-4 |n 10 |p 7830 - 7844 |t Molecular neurobiology |v 61 |y 2024 |x 0893-7648 |
| 856 | 4 | _ | |u https://pub.dzne.de/record/272839/files/DZNE-2024-01257.pdf |y OpenAccess |
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