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@ARTICLE{Schmitt:272839,
      author       = {Schmitt, Ina and Evert, Bernd O and Sharma, Amit and
                      Khazneh, Hassan and Murgatroyd, Chris and Wüllner, Ullrich},
      title        = {{T}he {A}lpha-{S}ynuclein {G}ene ({SNCA}) is a {G}enomic
                      {T}arget of {M}ethyl-{C}p{G} {B}inding {P}rotein 2
                      ({M}e{CP}2)-{I}mplications for {P}arkinson's {D}isease and
                      {R}ett {S}yndrome.},
      journal      = {Molecular neurobiology},
      volume       = {61},
      number       = {10},
      issn         = {0893-7648},
      address      = {Totowa, NJ},
      publisher    = {Humana Press},
      reportid     = {DZNE-2024-01257},
      pages        = {7830 - 7844},
      year         = {2024},
      abstract     = {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.},
      keywords     = {Methyl-CpG-Binding Protein 2: genetics / Methyl-CpG-Binding
                      Protein 2: metabolism / alpha-Synuclein: metabolism /
                      alpha-Synuclein: genetics / Humans / Rett Syndrome: genetics
                      / Rett Syndrome: metabolism / Cell Line, Tumor / Parkinson
                      Disease: genetics / Parkinson Disease: metabolism / DNA
                      Methylation: genetics / Protein Binding / Introns: genetics
                      / Mutation: genetics / SNCA (Other) / Alpha-synuclein
                      (Other) / DNA methylation (Other) / Epigenetic (Other) /
                      Genomic target (Other) / Intron (Other) / MeCP2 (Other) /
                      Methyl-CpG binding protein 2 (Other) / Parkinson’s disease
                      (Other) / RTT (Other) / Rett syndrome (Other) /
                      Methyl-CpG-Binding Protein 2 (NLM Chemicals) /
                      alpha-Synuclein (NLM Chemicals) / SNCA protein, human (NLM
                      Chemicals) / MECP2 protein, human (NLM Chemicals)},
      cin          = {AG Wüllner},
      ddc          = {570},
      cid          = {I:(DE-2719)1011302},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38429622},
      pmc          = {pmc:PMC11415397},
      doi          = {10.1007/s12035-024-03974-3},
      url          = {https://pub.dzne.de/record/272839},
}