Department of Cellular Signaling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
Mol Neurobiol. 2012 Aug;46(1):78-84. doi: 10.1007/s12035-012-8258-9. Epub 2012 Mar 20.
Poly(ADP-ribose) polymerase-1 (PARP-1) is a key enzyme responsible for the maintenance of genome stability, transcriptional regulation, and long-term potentiation in neurons. However, the excessive activation of PARP-1 under pathological conditions may lead to an accumulation of poly(ADP-ribose) (PAR), a novel signaling molecule that induces programmed cell death, or to NAD depletion that induces energy crisis and necrotic cell death. PARP-1 is thought to be primarily a nuclear enzyme, but some data indicate that it can also be localized to the mitochondria where it is responsible for posttranslational modification of electron transport chain complexes and alteration of mitochondria function. The enhancement of PARP-1 activity and the accumulation of PAR were demonstrated in the brain of patients with Alzheimer's disease (AD), particularly in neurons of the frontal and temporal lobes and in skin fibroblasts and lymphoblasts. Moreover, it has been reported that PARP-1 gene polymorphisms are highly associated with the development of AD. The activation of PARP-1 by oxidative stress seems to be an early and important event in the pathogenesis of AD. It is now widely accepted that the overproduction and oligomerization of amyloid β (Aβ) are responsible for the activation of a free radical cascade and oxidative stress in AD. Interestingly, the activity of PARP-1 is enhanced in AD and is also increased by Aβ peptides. The activation of PARP-1 by Aβ can lead to the PAR-mediated release of apoptosis-inducing factor from the mitochondria and its translocation to the nucleus, which leads to death of some populations of cells. A role of PARP-1 in the regulation of Aβ precursor protein metabolism processing and Aβ liberation has not been described previously. The study presented in this review indicated the relationship between PARP-1 activation, alteration of mitochondria function, and Aβ toxicity. The presented data should stimulate further studies on the role of PARP-1 in AD pathogenesis and thereby engage a new perspective regarding AD therapy.
聚（ADP-核糖）聚合酶 1（PARP-1）是一种关键的酶，负责维持基因组稳定性、转录调节和神经元中的长时程增强。然而，在病理条件下，PARP-1 的过度激活可能导致聚（ADP-核糖）（PAR）的积累，PAR 是一种新的信号分子，可诱导程序性细胞死亡，或 NAD 耗竭，导致能量危机和坏死性细胞死亡。PARP-1 被认为主要是一种核酶，但有些数据表明它也可以定位于线粒体，在那里它负责电子传递链复合物的翻译后修饰和改变线粒体功能。在阿尔茨海默病（AD）患者的大脑中，已经证明 PARP-1 活性的增强和 PAR 的积累，特别是在前额叶和颞叶的神经元以及皮肤成纤维细胞和淋巴母细胞中。此外，据报道，PARP-1 基因多态性与 AD 的发展高度相关。氧化应激对 PARP-1 的激活似乎是 AD 发病机制中的一个早期和重要事件。现在人们普遍认为，淀粉样β（Aβ）的过度产生和寡聚化是 AD 中自由基级联和氧化应激激活的原因。有趣的是，AD 中 PARP-1 的活性增强，Aβ 肽也会增加其活性。Aβ 对 PARP-1 的激活可导致 PAR 介导的凋亡诱导因子从线粒体释放并转移到细胞核，从而导致一些细胞群体死亡。PARP-1 在调节 Aβ 前体蛋白代谢加工和 Aβ 释放中的作用以前尚未描述过。本综述中提出的研究表明了 PARP-1 激活、线粒体功能改变和 Aβ 毒性之间的关系。所提供的数据应激发进一步研究 PARP-1 在 AD 发病机制中的作用，并为 AD 治疗提供新的视角。
