Promoter hypermethylation of the phosphatase DUSP22 mediates PKA-dependent TAU phosphorylation and CREB activation in Alzheimer's disease

• Published in: Hippocampus 2014-04, Vol.24 (4), p.363-368
• Main Authors: Sanchez-Mut, Jose Vicente, Aso, Ester, Heyn, Holger, Matsuda, Tadashi, Bock, Christoph, Ferrer, Isidre, Esteller, Manel
• Format: Article
• Language: English
• Subjects: ADN; Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; brain and neurodegeneration; Cell Line, Tumor; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; DNA; DNA methylation; Dual-Specificity Phosphatases - genetics; Dual-Specificity Phosphatases - metabolism; Epigenesis; Epigenesis, Genetic; epigenetics; Epigènesi; Female; Gene Expression; Hipocamp (Cervell); hippocampus; Hippocampus (Brain); Hippocampus - metabolism; Humans; Malaltia d'Alzheimer; Malalties neurodegeneratives; Male; Methylation; Metilació; Mitogen-Activated Protein Kinase Phosphatases - genetics; Mitogen-Activated Protein Kinase Phosphatases - metabolism; Neurodegenerative diseases; Phosphorylation; Promoter Regions, Genetic - physiology; Rapid Communication; Signal Transduction - physiology; tau Proteins - metabolism
• ISSN: 1050-9631; 1098-1063
• DOI: 10.1002/hipo.22245

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. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.