Ina Schmitt1,2, Oliver Kaut1, Hassan Khazneh1, Laura deBoni1, Ashar Ahmad3, Daniela Berg2,4, Christine Klein5, Holger Fröhlich3, Ullrich Wüllner1,2. 1. Department of Neurology, UKB, Bonn, Germany. 2. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. 3. Bonn-Aachen International Center for IT, University of Bonn, Germany. 4. Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Tübingen, Germany. 5. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
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.
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 PDpatients 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 PDpatients, 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 PDpatients 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 PDpatients' 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: Adrienne Henderson-Smith; Kathleen M Fisch; Jianping Hua; Ganqiang Liu; Eugenia Ricciardelli; Kristen Jepsen; Mathew Huentelman; Gabriel Stalberg; Steven D Edland; Clemens R Scherzer; Travis Dunckley; Paula Desplats Journal: Epigenetics Date: 2019-03-14 Impact factor: 4.528
Authors: Ke-Xin Wen; Jelena Miliç; Bassem El-Khodor; Klodian Dhana; Jana Nano; Tammy Pulido; Bledar Kraja; Asija Zaciragic; Wichor M Bramer; John Troup; Rajiv Chowdhury; M Arfam Ikram; Abbas Dehghan; Taulant Muka; Oscar H Franco Journal: PLoS One Date: 2016-12-14 Impact factor: 3.240
Authors: Laura de Boni; Gilles Gasparoni; Carolin Haubenreich; Sascha Tierling; Ina Schmitt; Michael Peitz; Philipp Koch; Jörn Walter; Ullrich Wüllner; Oliver Brüstle Journal: Clin Epigenetics Date: 2018-01-29 Impact factor: 6.551