%0 Journal Article
%A Schmitt, Ina
%A Evert, Bernd O
%A Sharma, Amit
%A Khazneh, Hassan
%A Murgatroyd, Chris
%A Wüllner, Ullrich
%T The Alpha-Synuclein Gene (SNCA) is a Genomic Target of Methyl-CpG Binding Protein 2 (MeCP2)-Implications for Parkinson's Disease and Rett Syndrome.
%J Molecular neurobiology
%V 61
%N 10
%@ 0893-7648
%C Totowa, NJ
%I Humana Press
%M DZNE-2024-01257
%P 7830 - 7844
%D 2024
%X 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
%K Methyl-CpG-Binding Protein 2: genetics
%K Methyl-CpG-Binding Protein 2: metabolism
%K alpha-Synuclein: metabolism
%K alpha-Synuclein: genetics
%K Humans
%K Rett Syndrome: genetics
%K Rett Syndrome: metabolism
%K Cell Line, Tumor
%K Parkinson Disease: genetics
%K Parkinson Disease: metabolism
%K DNA Methylation: genetics
%K Protein Binding
%K Introns: genetics
%K Mutation: genetics
%K SNCA (Other)
%K Alpha-synuclein (Other)
%K DNA methylation (Other)
%K Epigenetic (Other)
%K Genomic target (Other)
%K Intron (Other)
%K MeCP2 (Other)
%K Methyl-CpG binding protein 2 (Other)
%K Parkinson’s disease (Other)
%K RTT (Other)
%K Rett syndrome (Other)
%K Methyl-CpG-Binding Protein 2 (NLM Chemicals)
%K alpha-Synuclein (NLM Chemicals)
%K SNCA protein, human (NLM Chemicals)
%K MECP2 protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:38429622
%2 pmc:PMC11415397
%R 10.1007/s12035-024-03974-3
%U https://pub.dzne.de/record/272839