title: Alpha-synuclein sequesters Dnmt1 from the nucleus: a novel mechanism for epigenetic alterations in Lewy body diseases.
abstract: DNA methylation is a major epigenetic modification that regulates gene expression. Dnmt1, the maintenance DNA methylation enzyme, is abundantly expressed in the adult brain and is mainly located in the nuclear compartment, where it has access to chromatin. Hypomethylation of CpG islands at intron 1 of the SNCA gene has recently been reported to result in overexpression of α-synuclein in Parkinson disease (PD) and related disorders. We therefore investigated the mechanisms underlying altered DNA methylation in PD and dementia with Lewy bodies (DLB). We present evidence of reduction of nuclear Dnmt1 levels in human postmortem brain samples from PD and DLB patients as well as in the brains of α-synuclein transgenic mice models. Furthermore, sequestration of Dnmt1 in the cytoplasm results in global DNA hypomethylation in human and mouse brains, involving CpG islands upstream of SNCA, SEPW1, and PRKAR2A genes. We report that association of Dnmt1 and α-synuclein might mediate aberrant subcellular localization of Dnmt1. Nuclear Dnmt1 levels were partially rescued by overexpression of Dnmt1 in neuronal cell cultures and in α-synuclein transgenic mice brains. Our results underscore a novel mechanism for epigenetic dysregulation in Lewy body diseases, which might underlie the decrease in DNA methylation reported for PD and DLB.
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA. pdesplat@ucsd.edu
authors.forename: Paula
authors.initials: P
authors.lastname: Desplats
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Coffee
authors.forename: Pruthul
authors.initials: P
authors.lastname: Patel
authors.forename: Sarah
authors.initials: S
authors.lastname: Michael
authors.forename: Christina
authors.initials: C
authors.lastname: Patrick
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism*; D018899:CpG Islands; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit / Q000235:genetics / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D020961:Lewy Body Disease / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051151:Selenoprotein W / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; C517819:PRKAR2A protein, human; C517821:Prkar2a protein, mouse; C495240:SELENOW protein, human; C497604:SNCA protein, human; D051151:Selenoprotein W; C497605:Snca protein, mouse; D051844:alpha-Synuclein; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse