A role for p53 in the β-amyloid-mediated regulation of the lysosomal system

被引:26
作者
Fogarty, Marie P.
McCormack, Roisin M.
Noonan, Janis
Murphy, Declan
Gowran, Aoife
Campbell, Veronica A. [1 ]
机构
[1] Univ Dublin Trinity Coll, Dept Physiol, Dublin 2, Ireland
关键词
beta-Amyloid; Lysosome; p53; Apoptosis; CULTURED CORTICAL-NEURONS; MITOCHONDRIAL-MEMBRANE PERMEABILIZATION; ALZHEIMERS-DISEASE; CELL-DEATH; APOPTOTIC CASCADE; APOLIPOPROTEIN E4; BAX EXPRESSION; CATHEPSIN-L; ACTIVATION; PEPTIDE;
D O I
10.1016/j.neurobiolaging.2008.09.018
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
beta-Amyloid accumulates around neurons in Alzheimer's disease and is thought to contribute to the neurodegenerative process. This study examined the role of the tumour suppressor protein, p53, in the neurodegenerative pathway, with focus on the interaction of p53 with the lysosomal system. beta-Amyloid increased expression of p53 and its transcription target, Bax, in cultured cortical neurons. In addition, A beta increased the association of phospho-p53(ser15) with the lysosomal compartment and this correlated with destabilization of the lysosomal membrane and a concomitant increase in cytosolic cathepsin-L activity. These effects of beta-amyloid were abolished by the p53 inhibitor, pifithrin-alpha, and siRNA-mediated knockdown of p53, demonstrating that p53 is a critical regulator of lysosomal integrity and the induction of cathepsin-L protease activity. In addition, activation of the apoptotic cascade was abolished by pifithrin-alpha. We conclude that p53 associates with the lysosome to regulate a lysosomal branch of the apoptotic cascade which contributes to beta-amyloid-mediated neurodegeneration. (C) 2008 Elsevier Inc. All rights reserved.
引用
收藏
页码:1774 / 1786
页数:13
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