title: L-dopa increases α-synuclein DNA methylation in Parkinson's disease patients in vivo and in vitro.
abstract: BACKGROUND
  Increasing gene dosages of α-synuclein induce familial Parkinson's disease (PD); thus, the hypothesis has been put forward that regulation of gene expression, in particular altered α-synuclein gene methylation, might be associated with sporadic PD and could be used as a biological marker.
  
  
  METHODS
  We performed a thorough analysis of α-synuclein methylation in bisulfite-treated DNA from peripheral blood of 490 sporadic PD patients and 485 healthy controls and in addition analyzed the effect of levodopa (L-dopa) on α-synuclein methylation and expression in cultured mononuclear cells.
  
  
  RESULTS
  α-Synuclein was hypomethylated in sporadic PD patients, correlated with sex, age, and a polymorphism in the analyzed sequence stretch (rs3756063). α-Synuclein methylation separated healthy individuals from sporadic PD with a specificity of 74% (male) and 78% (female), respectively. α-Synuclein methylation was increased in sporadic PD patients with higher l-dopa dosage, and L-dopa specifically induced methylation of α-synuclein intron 1 in cultured mononuclear cells.
  
  
  CONCLUSIONS
  α-Synuclein methylation levels depended on disease status, sex, age, and the genotype of rs3756063. The pharmacological action of L-dopa was not limited to the dopamine precursor function but included epigenetic off-target effects. The hypomethylation of α-synuclein in sporadic PD patients' blood already observed in previous studies was probably underestimated because of effect of L-dopa, which was not known previously. The analysis of α-synuclein methylation can help to identify nonparkinsonian individuals with reasonable specificity, which offers a valuable tool for researchers and clinicians.
authors.affiliation: Department of Neurology, UKB, Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Schmitt
authors.affiliation: Department of Neurology, UKB, Bonn, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kaut
authors.affiliation: Department of Neurology, UKB, Bonn, Germany.
authors.forename: Hassan
authors.initials: H
authors.lastname: Khazneh
authors.affiliation: Department of Neurology, UKB, Bonn, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: deBoni
authors.affiliation: Bonn-Aachen International Center for IT, University of Bonn, Germany.
authors.forename: Ashar
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Tübingen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: Bonn-Aachen International Center for IT, University of Bonn, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Fröhlich
authors.affiliation: Department of Neurology, UKB, Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Ullrich
authors.initials: U
authors.lastname: Wüllner
mesh_terms: D000367:Age Factors; D000368:Aged; D002478:Cells, Cultured; D018899:CpG Islands / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D015259:Dopamine Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D006801:Humans; D007980:Levodopa / Q000494:pharmacology* / Q000627:therapeutic use; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D012372:ROC Curve; D012044:Regression Analysis; D012737:Sex Factors; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D015259:Dopamine Agents; D051844:alpha-Synuclein; D007980:Levodopa
keywords: DNA methylation; Parkinson's disease; blood; l-dopa; α-synuclein