Zyxin is a novel target for beta-amyloid peptide: Characterization of its role in Alzheimer's pathogenesis

Abstract

Zyxin is an adaptor protein recently identified as a novel regulator of the homeodomain-interacting protein kinase 2 (HIPK2)-p53 signaling in response to DNA damage. We recently reported an altered conformational state of p53 in tissues from patients with Alzheimer 's disease (AD), because of a deregulation of HIPK2 activity, leading to an impaired and dysfunctional response to stressors. Here, we examined the molecular mechanisms underlying the deregulation of HIPK2 activity in two cellular models, HEK-293 cells and SH-SY5Y neuroblastoma cells differentiated with retinoic acid over-expressing the amyloid precursor protein, focusing on the evidence that zyxin expression is important to maintain HIPK2 protein stability. We demonstrated that both beta-amyloid (Aβ) 1-40 and 1-42 induce zyxin deregulation, thus affecting the transcriptional repressor activity of HIPK2 onto its target promoter, metallothionein 2A, which is in turn responsible for the induction of an altered conformational state of p53. We demonstrate for the first time that zyxin is a novel target of Aβ activities in AD. These results may help the studies on the pathogenesis of AD, through the fine dissection of events related to beta-amyloid activities. Putative role of zyxin in Alzheimer pathogenesis Soluble Aβ modulates zyxin protein levels, fundamental in maintaining HIPK2 stability and p53 activity. When zyxin is down-regulated by Aβ peptides, HIPK2 activity is inhibited, thus inducing an altered conformational state of p53. These results may help the studies on Alzheimer pathogenesis, through the fine dissection of events related to Aβ activities. © 2013 International Society for Neurochemistry.