title: Promoter hypermethylation of the phosphatase DUSP22 mediates PKA-dependent TAU phosphorylation and CREB activation in Alzheimer's disease.
abstract: Genetic screening in Alzheimer's disease (AD) has identified only a handful of genes that are mutated in the disorder. Thus, for a very large proportion of patients, the biology of their disease is poorly understood. Epigenetic alterations may provide an explanation in these cases. Using DNA methylation profiles of human hippocampus from controls and patients, we have identified the presence of promoter hypermethylation of the dual-specificity phosphatase 22 (DUSP22) gene in AD. DUSP22 is a likely candidate gene for involvement in the pathogenesis of the disorder since, as we demonstrate here, it inhibits PKA activity and thereby determines TAU phosphorylation status and CREB signaling.
authors.affiliation: Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Jose Vicente
authors.initials: JV
authors.lastname: Sanchez-Mut
authors.forename: Ester
authors.initials: E
authors.lastname: Aso
authors.forename: Holger
authors.initials: H
authors.lastname: Heyn
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuda
authors.forename: Christoph
authors.initials: C
authors.lastname: Bock
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D008745:Methylation; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C054369:MAPT protein, human; D016875:tau Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; C442824:DUSP22 protein, human; D054637:Dual-Specificity Phosphatases
keywords: DNA methylation; brain and neurodegeneration; epigenetics; hippocampus