title: c-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease.
abstract: In Alzheimer's disease (AD), there is a decrease in neuronal gene expression induced by HDAC2 increase; however, the mechanisms involved are not fully elucidated. Here, we described how the tyrosine kinase c-Abl increases HDAC2 levels, inducing transcriptional repression of synaptic genes. Our data demonstrate that (1) in neurons, c-Abl inhibition with Imatinib prevents the AβO-induced increase in HDAC2 levels; (2) c-Abl knockdown cells show a decrease in HDAC2 levels, while c-Abl overexpression increases them; (3) c-Abl inhibition reduces HDAC2-dependent repression activity and HDAC2 recruitment to the promoter of several synaptic genes, increasing their expression; (4) c-Abl induces tyrosine phosphorylation of HDAC2, a posttranslational modification, affecting both its stability and repression activity; and (5) treatment with Imatinib decreases HDAC2 levels in a transgenic mice model of AD. Our results support the participation of the c-Abl/HDAC2 signaling pathway in the epigenetic blockade of gene expression in AD pathology.
authors.affiliation: Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile; Biological and Chemistry Sciences Department, Universidad Bernardo O'Higgins, Santiago 8370993, Chile.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Gonzalez-Zuñiga
authors.affiliation: Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile; Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.
authors.forename: Pablo S
authors.initials: PS
authors.lastname: Contreras
authors.affiliation: Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile; Biological and Chemistry Sciences Department, Universidad Bernardo O'Higgins, Santiago 8370993, Chile.
authors.forename: Lisbell D
authors.initials: LD
authors.lastname: Estrada
authors.affiliation: Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.
authors.forename: David
authors.initials: D
authors.lastname: Chamorro
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Villagra
authors.affiliation: Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.
authors.forename: Silvana
authors.initials: S
authors.lastname: Zanlungo
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
authors.affiliation: Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile. Electronic address: aalvarez@bio.puc.cl.
authors.forename: Alejandra R
authors.initials: AR
authors.lastname: Alvarez
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006367:HeLa Cells; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2