TY  - JOUR
AU  - Schmitt, Ina
AU  - Evert, Bernd O
AU  - Sharma, Amit
AU  - Khazneh, Hassan
AU  - Murgatroyd, Chris
AU  - Wüllner, Ullrich
TI  - The Alpha-Synuclein Gene (SNCA) is a Genomic Target of Methyl-CpG Binding Protein 2 (MeCP2)-Implications for Parkinson's Disease and Rett Syndrome.
JO  - Molecular neurobiology
VL  - 61
IS  - 10
SN  - 0893-7648
CY  - Totowa, NJ
PB  - Humana Press
M1  - DZNE-2024-01257
SP  - 7830 - 7844
PY  - 2024
AB  - 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
KW  - Methyl-CpG-Binding Protein 2: genetics
KW  - Methyl-CpG-Binding Protein 2: metabolism
KW  - alpha-Synuclein: metabolism
KW  - alpha-Synuclein: genetics
KW  - Humans
KW  - Rett Syndrome: genetics
KW  - Rett Syndrome: metabolism
KW  - Cell Line, Tumor
KW  - Parkinson Disease: genetics
KW  - Parkinson Disease: metabolism
KW  - DNA Methylation: genetics
KW  - Protein Binding
KW  - Introns: genetics
KW  - Mutation: genetics
KW  - SNCA (Other)
KW  - Alpha-synuclein (Other)
KW  - DNA methylation (Other)
KW  - Epigenetic (Other)
KW  - Genomic target (Other)
KW  - Intron (Other)
KW  - MeCP2 (Other)
KW  - Methyl-CpG binding protein 2 (Other)
KW  - Parkinson’s disease (Other)
KW  - RTT (Other)
KW  - Rett syndrome (Other)
KW  - Methyl-CpG-Binding Protein 2 (NLM Chemicals)
KW  - alpha-Synuclein (NLM Chemicals)
KW  - SNCA protein, human (NLM Chemicals)
KW  - MECP2 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38429622
C2  - pmc:PMC11415397
DO  - DOI:10.1007/s12035-024-03974-3
UR  - https://pub.dzne.de/record/272839
ER  -