Inhibition of Poly(ADP-ribose) Polymerase-1 Enhances Gene Expression of Selected Sirtuins and APP Cleaving Enzymes in Amyloid Beta Cytotoxicity.
Inhibition of Poly(ADP-ribose) Polymerase-1 Enhances Gene Expression of Selected Sirtuins and APP Cleaving Enzymes in Amyloid Beta Cytotoxicity.
复制标题
DOI：
10.1007/s12035-017-0646-8
复制
发表时间：
2018-06
影响因子：
5.1
通讯作者：
Strosznajder RP
中科院分区：
文献类型：
--
作者：
Wencel PL;Lukiw WJ;Strosznajder JB;Strosznajder RP
聚（ADP-核糖）聚合酶（PARP）和沉默调节蛋白（SIRTs）参与细胞代谢、转录和DNA修复的调节。这些酶的改变可能在阿尔茨海默病（AD）中起着至关重要的作用。我们以前的研究结果表明，淀粉样β（Aβ）肽和炎症导致PARP 1激活和细胞死亡。本研究旨在探讨PARP 1在Aβ42寡聚体（AβO）毒性下对嗜铬细胞瘤细胞（PC 12）SIRT和β-淀粉样前体蛋白（βAPP）裂解酶基因表达的调节作用。此外，分析了内源性释放的Aβ肽在稳定转染人APP野生型基因（APPwt）的PC 12细胞中的作用。我们的结果表明，AβO增强早老素（Psen 1和Psen 2）的转录，这是γ-分泌酶的关键亚基。APPwt细胞中的Aβ肽激活β-分泌酶（Bace 1）、Psen 1、Psen 2和Parp 1的表达。PARP 1抑制剂PJ-34在AβO存在下上调α-分泌酶（Adam 10）、Psen 1和Psen 2的转录，但也上调Bace 1的转录。同时，PJ-34还能提高AβOs诱导的PC 12细胞核Sirt 1、Sirt 6、线粒体Sirt 4和Parp 3的mRNA水平。提示Aβ肽通过调节APP分泌酶，可能导致恶性代谢循环，维持Aβ高水平。PARP 1抑制除了激活核SIRTs和线粒体Sirt 4表达外，还增强了参与βAPP代谢的酶的转录，在其抗Aβ肽毒性的应用中应考虑这种作用。
Poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs) are involved in the regulation of cell metabolism, transcription, and DNA repair. Alterations of these enzymes may play a crucial role in Alzheimer’s disease (AD). Our previous results indicated that amyloid beta (Aβ) peptides and inflammation led to activation of PARP1 and cell death. This study focused on a role of PARP1 in the regulation of gene expression for SIRTs and beta-amyloid precursor protein (βAPP) cleaving enzymes under Aβ42 oligomers (AβO) toxicity in pheochromocytoma cells (PC12) in culture. Moreover, the effect of endogenously liberated Aβ peptides in PC12 cells stably transfected with human gene for APP wild-type (APPwt) was analyzed. Our results demonstrated that AβO enhanced transcription of presenilins (Psen1 and Psen2), the crucial subunits of γ-secretase. Aβ peptides in APPwt cells activated expression of β-secretase (Bace1), Psen1, Psen2, and Parp1. The inhibitor of PARP1, PJ-34 in the presence of AβO upregulated transcription of α-secretase (Adam10), Psen1, and Psen2, but also Bace1. Concomitantly, PJ-34 enhanced mRNA level of nuclear Sirt1, Sirt6, mitochondrial Sirt4, and Parp3 in PC12 cells subjected to AβOs toxicity. Our data indicated that Aβ peptides through modulation of APP secretases may lead to a vicious metabolic circle, which could be responsible for maintaining Aβ at high level. PARP1 inhibition, besides activation of nuclear SIRTs and mitochondrial Sirt4 expression, enhanced transcription of enzyme(s) involved in βAPP metabolism, and this effect should be considered in its application against Aβ peptide toxicity.
登录
查看更多内容
影响因子：
29
作者：
Bai P;Canto C;Brunyánszki A;Huber A;Szántó M;Cen Y;Yamamoto H;Houten SM;Kiss B;Oudart H;Gergely P;Menissier-de Murcia J;Schreiber V;Sauve AA;Auwerx J
通讯作者：
Auwerx J
影响因子：
48
作者：
Bonda, David J.;Lee, Hyoung-gon;Camins, Antoni;Pallas, Merce;Casadesus, Gemma;Smith, Mark A.;Zhu, Xiongwei
通讯作者：
Zhu, Xiongwei
影响因子：
5.7
作者：
Felici, Roberta;Cavone, Leonardo;Chiarugi, Alberto
通讯作者：
Chiarugi, Alberto
影响因子：
3.6
作者：
Bayrakdar, Ezgi Turunc;Armagan, Guliz;Yalcin, Ayfer
通讯作者：
Yalcin, Ayfer
影响因子：
25
作者：
Cleary, JP;Walsh, DM;Ashe, KH
通讯作者：
Ashe, KH