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.

Histone deacetylases in memory and cognition

“…HDAC2 abundance was increased in parallel with plasticity and acetylation changes in multiple AD mouse models and could be induced by amyloid b (Ab) (Fig. 1) (55,56,58). Furthermore, examination of postmortem samples from AD patients revealed that HDAC2 abundance was substantially increased even at the earliest stages of AD pathology, suggesting that HDAC2 could be a driver of cognitive decline in this disease (55).…”

Role for Tyrosine Phosphorylation of A-kinase Anchoring Protein 8 (AKAP8) in Its Dissociation from Chromatin and the Nuclear Matrix

“…However, a limited number of studies showed the functions of the tyrosine kinases present in the nucleus (1,2,12,14,22,53,54). Because tyrosine kinases are largely located at the plasma membrane and the cytoplasm, tyrosine phosphorylation signals have been hardly detected in the nucleus.…”

“…In addition, the association of AKAP8 with nuclear structures is involved in gene expression, DNA replication, and mitotic progression (26,56,57). Recently, the nuclear proteins KAT5, histone H4, and HDAC2 were reported to be tyrosinephosphorylated and to functionally associate with chromatin structures (22,54,58). Taken together, we assume that tyrosine phosphorylation of various nuclear proteins, including AKAP8, is attributable to nuclear tyrosine kinase-mediated chromatin structural changes, which could be involved in a variety of nuclear function, such as gene expression, DNA replication, and mitotic progression.…”

Histone acetylation in neuronal (dys)function

“…However, what causes increases of HDAC activity in AD remains to be determined. It has been shown that amyloid β may activate c-Abl, which in turn phosphorylates HDAC 2, thereby preventing its poly-ubiquitinylation and subsequent degradation by the proteasome (85). Another identified mechanism of HDAC increase is stress.…”