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Alterations in the levels of cellular a-syn have been hypothesized to play a critical role in the development of Parkinson\u2019s disease (PD); however, mechanisms that control expression of the gene for a-syn (\n                    <jats:italic>SNCA<\/jats:italic>\n                    ) in\n                    <jats:italic>cis<\/jats:italic>\n                    and\n                    <jats:italic>trans<\/jats:italic>\n                    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\n                    <jats:italic>SNCA<\/jats:italic>\n                    gene and regulates a-syn protein expression\n                    <jats:italic>.<\/jats:italic>\n                    Chromatin immunoprecipitation (ChIP) and electrophoretic mobility-shift assays (EMSA) were used to confirm binding of MeCP2 to regulatory regions of\n                    <jats:italic>SNCA<\/jats:italic>\n                    . 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\n                    <jats:italic>SNCA<\/jats:italic>\n                    regulation was further investigated by overexpressing MeCP2 and mutated variants of MeCP2 in\n                    <jats:italic>MeCP2<\/jats:italic>\n                    knockout cells. We found that methylation-dependent binding of MeCP2 at a restricted region of intron 1 of\n                    <jats:italic>SNCA<\/jats:italic>\n                    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\n                    <jats:italic>SNCA<\/jats:italic>\n                    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\n                    <jats:italic>MeCP2<\/jats:italic>\n                    in SK-N-SH cells resulted in a significant increase in a-syn production, demonstrating that\n                    <jats:italic>SNCA<\/jats:italic>\n                    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\n                    <jats:italic>SNCA<\/jats:italic>\n                    gene plays an important role in the control of a-syn expression. In addition, the changes in\n                    <jats:italic>SNCA<\/jats:italic>\n                    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\n                    <jats:italic>MECP2<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1007\/s12035-024-03974-3","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T22:01:35Z","timestamp":1709330495000},"page":"7830-7844","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The Alpha-Synuclein Gene (SNCA) is a Genomic Target of Methyl-CpG Binding Protein 2 (MeCP2)\u2014Implications for Parkinson\u2019s Disease and Rett Syndrome"],"prefix":"10.1007","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8818-710X","authenticated-orcid":false,"given":"Ina","family":"Schmitt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3443-4096","authenticated-orcid":false,"given":"Bernd O.","family":"Evert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2216-5389","authenticated-orcid":false,"given":"Amit","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Khazneh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6885-7794","authenticated-orcid":false,"given":"Chris","family":"Murgatroyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3132-0790","authenticated-orcid":false,"given":"Ullrich","family":"W\u00fcllner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,2]]},"reference":[{"key":"3974_CR1","doi-asserted-by":"crossref","first-page":"116","DOI":"10.3389\/fnins.2020.00116","volume":"14","author":"RG Perez","year":"2020","unstructured":"Perez RG (2020) Editorial: The protein alpha-synuclein: its normal role (in neurons) and its role in disease. 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