CHIP stabilizes amyloid precursor protein via proteasomal degradation and p53-mediated trans-repression of β-secretase

Aging Cell
Amir Kumar Singh, Uttam Pati

Abstract

In patient with Alzheimer's disease (AD), deposition of amyloid-beta Aβ, a proteolytic cleavage of amyloid precursor protein (APP) by β-secretase/BACE1, forms senile plaque in the brain. BACE1 activation is caused due to oxidative stresses and dysfunction of ubiquitin-proteasome system (UPS), which is linked to p53 inactivation. As partial suppression of BACE1 attenuates Aβ generation and AD-related pathology, it might be an ideal target for AD treatment. We have shown that both in neurons and in HEK-APP cells, BACE1 is a new substrate of E3-ligase CHIP and an inverse relation exists between CHIP and BACE1 level. CHIP inhibits ectopic BACE1 level by promoting its ubiquitination and proteasomal degradation, thus reducing APP processing; it stabilizes APP in neurons, thus reducing Aβ. CHIP(U) (box) domain physically interacts with BACE1; however, both U-box and TPR domain are essential for ubiquitination and degradation of BACE1. Further, BACE1 is a downstream target of p53 and overexpression of p53 decreases BACE1 level. In HEK-APP cells, CHIP is shown to negatively regulate BACE1 promoter through stabilization of p53's DNA-binding conformation and its binding upon 5' UTR element (+127 to +150). We have thus discovered that CHIP...Continue Reading

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Citations

Feb 10, 2016·Frontiers in Molecular Neuroscience·Bing GongChristopher Cardozo
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Jan 14, 2021·International Journal of Biological Macromolecules·Marjan TalebiSaeed Samarghandian
May 25, 2021·The Journal of Biological Chemistry·Bénédicte GaboritFranck Peiretti

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Methods Mentioned

BETA
ubiquitination
co-immunoprecipitation
PCR
immunoprecipitation
ChIP
transfection
transfections
PCRs

Software Mentioned

GeneTools
GeneSnap
MatInspector
Sigma Plot

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