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000272839 041__ $$aEnglish
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000272839 1001_ $$0P:(DE-2719)2810444$$aSchmitt, Ina$$b0$$eFirst author
000272839 245__ $$aThe Alpha-Synuclein Gene (SNCA) is a Genomic Target of Methyl-CpG Binding Protein 2 (MeCP2)-Implications for Parkinson's Disease and Rett Syndrome.
000272839 260__ $$aTotowa, NJ$$bHumana Press$$c2024
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000272839 520__ $$aMounting 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.
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000272839 650_7 $$2Other$$aSNCA
000272839 650_7 $$2Other$$aAlpha-synuclein
000272839 650_7 $$2Other$$aDNA methylation
000272839 650_7 $$2Other$$aEpigenetic
000272839 650_7 $$2Other$$aGenomic target
000272839 650_7 $$2Other$$aIntron
000272839 650_7 $$2Other$$aMeCP2
000272839 650_7 $$2Other$$aMethyl-CpG binding protein 2
000272839 650_7 $$2Other$$aParkinson’s disease
000272839 650_7 $$2Other$$aRTT
000272839 650_7 $$2Other$$aRett syndrome
000272839 650_7 $$2NLM Chemicals$$aMethyl-CpG-Binding Protein 2
000272839 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000272839 650_7 $$2NLM Chemicals$$aSNCA protein, human
000272839 650_7 $$2NLM Chemicals$$aMECP2 protein, human
000272839 650_2 $$2MeSH$$aMethyl-CpG-Binding Protein 2: genetics
000272839 650_2 $$2MeSH$$aMethyl-CpG-Binding Protein 2: metabolism
000272839 650_2 $$2MeSH$$aalpha-Synuclein: metabolism
000272839 650_2 $$2MeSH$$aalpha-Synuclein: genetics
000272839 650_2 $$2MeSH$$aHumans
000272839 650_2 $$2MeSH$$aRett Syndrome: genetics
000272839 650_2 $$2MeSH$$aRett Syndrome: metabolism
000272839 650_2 $$2MeSH$$aCell Line, Tumor
000272839 650_2 $$2MeSH$$aParkinson Disease: genetics
000272839 650_2 $$2MeSH$$aParkinson Disease: metabolism
000272839 650_2 $$2MeSH$$aDNA Methylation: genetics
000272839 650_2 $$2MeSH$$aProtein Binding
000272839 650_2 $$2MeSH$$aIntrons: genetics
000272839 650_2 $$2MeSH$$aMutation: genetics
000272839 7001_ $$00009-0002-3443-4096$$aEvert, Bernd O$$b1
000272839 7001_ $$00000-0002-2216-5389$$aSharma, Amit$$b2
000272839 7001_ $$aKhazneh, Hassan$$b3
000272839 7001_ $$00000-0002-6885-7794$$aMurgatroyd, Chris$$b4
000272839 7001_ $$0P:(DE-2719)2000056$$aWüllner, Ullrich$$b5$$eLast author
000272839 773__ $$0PERI:(DE-600)2079384-4$$a10.1007/s12035-024-03974-3$$gVol. 61, no. 10, p. 7830 - 7844$$n10$$p7830 - 7844$$tMolecular neurobiology$$v61$$x0893-7648$$y2024
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