The Effect Of CHIP On PS1 Stability

Alzheimer's disease(AD) is a progressive neurodegenerative disorder characterized by cognitive decline and progressive memory loss.AD has two pathological hallmarks in the brain:neurofibrillary tangle(NFT) and senile plaque (SP).Senile plaques are composed ofβ-amyloid(Aβ) peptide,which is derived from its precursor protein APP through sequential cleavages byβ- andγ-secretases.γ-secretase is a high molecular weight complex consisting at least four components: Presenilin(PS,including PS1 and PS2),nicastrin,APH-1 and PEN-2.Among them, PS1 functions as the catalytic center of theγ-secretase and is indispensable for the generation of Aβ.Our lab has identified that CHIP(carboxyl terminus of Hsc70-interacting protein) can interact with PS1 through its TRP domain by yeast two-hybrid system and co-immunoprecipitantion in HEK 293T cells.CHIP is a ubiquitin ligase that mediates degradation of misfolded or unstable proteins through the ubiquitin-protease system. In addition,CHIP can function as a chaperone and stabilize proteins.To further elucidate the biological relevance of the interaction between CHIP and PS1 and its potential role in Alzheimer Disease,we studied the effects of CHIP on PS1/γ-secretase stability and enzymatic activity as well as APP processing.Out results show that overexpression of CHIP does not enhance the ubiquitination level of PS1 through its U-box domain but can stabilize exogenous full length PS1 and endogenous PS1-CTF and PS1-NTF.Moreover,overexpression of CHIP can increase Aβproduction andγ-secretase cleavage of Notch for NICD generation.Together our results suggest that CHIP can regulateγ-secretase activity through its interaction with PS1.