Linking Defects in DNA Repair to Mitochondrial Dysfunction in Alzheimer's Disease

阿尔茨海默病(AD)是一种破坏性的神经系统疾病，与认知功能的进行性丧失以及体力和心理技能的进行性丧失有关。我们和其他人观察到，在包括阿尔茨海默病在内的几种人类病理情况下，DNA修复缺陷与线粒体功能障碍有关。也有强有力的证据表明，线粒体功能障碍是阿尔茨海默病显著的神经病理特征，AD患者脑神经元中积累了高水平的氧化应激和DNA损伤。此外，现在人们普遍认为，持续的DNA损伤会导致聚(ADP-核糖)聚合酶-1(PARP1)的慢性激活，进而引发一系列下游事件，包括烟酰胺腺嘌呤二核苷酸(NAD+)的耗尽、sirtuins的抑制以及细胞生物能量学的改变。在AD患者和抑制PARP1或增加NAD+部分逆转AD细胞模型表型变化的药物中，PARP1被过度激活。重要的是，我们最近表明，NAD+的耗尽和随后的补充可以改变AD病理的关键方面，如tau磷酸化和DNA损伤积累。基于这些观察，我们建议研究AD病理、NAD+持续枯竭、有丝分裂缺陷、线粒体功能障碍和DNA修复改变或缺陷之间的复杂关系。

Alzheimers disease (AD) is a devastating neurological disease associated with progressive loss of cognitive function as well as progressive loss of physical and mental skills. We and others have observed that defects in DNA repair correlate with mitochondrial dysfunction in the context of several human pathological conditions, including AD. There is also strong evidence that mitochondrial dysfunction contributes to prominent neuropathological features of AD and that high levels of oxidative stress and DNA damage accumulate in brain neurons from AD patients. Furthermore, it is now widely-accepted that persistent DNA damage leads to chronic activation of poly (ADP-ribose) polymerase-1 (PARP1), which in turn triggers a series of downstream events including depletion of nicotinamide adenine dinucleotide (NAD+), inhibition of Sirtuins, and altered cellular bioenergetics. PARP1 is hyper-activated in neurons of AD patients and agents that inhibit PARP1 or increase NAD+ partially reverse phenotypic changes in cellular models of AD. Importantly, we have recently shown that depletion of NAD+ and its subsequent replenishment can alter critical aspects of AD pathology like tau phosphorylation and DNA damage accumulation. Based on these observations, we propose to, investigate the complex relationships between AD pathology, persistent depletion of NAD+, defective mitophagy, mitochondrial dysfunction, and altered or defective DNA repair.