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Mol Cell. 2014 Oct 2;56(1):163-73. doi: 10.1016/j.molcel.2014.08.013. Epub 2014 Sep 11.

c-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease.

Author information

1
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.
2
Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile; Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.
3
Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.
4
Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
5
Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.
6
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
7
Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile. Electronic address: aalvarez@bio.puc.cl.

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.

PMID:
25219501
DOI:
10.1016/j.molcel.2014.08.013
[Indexed for MEDLINE]
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