DNA repair dysfunction in neurodegeneration and Alzheimer's Disease

我们的目标是确定氧化DNA损伤的形成或处理过程中的变化是否与神经变性和阿尔茨海默病(AD)有关。我们的假设是，DNA修复系统在应对多种类型的急性和慢性细胞应激中发挥关键作用。我们已经确定了从PARP1到有丝分裂缺陷的DNA损伤反应级联反应。在罕见的常染色体隐性遗传性疾病共济失调毛细血管扩张症(AT)中，我们发现多个物种的PAR化增加、NAD+降低和线粒体功能障碍。重要的是，恢复NAD水平的NAD+前体治疗降低了AT神经病理的严重程度，改善了神经肌肉功能，延缓了记忆丧失，并显著延长了寿命。从机制上讲，我们将这些好处归因于DNA修复和有丝分裂能力的改善。这项工作强调了DNA修复和线粒体功能之间的重要联系，并进一步指出了新的治疗干预措施。 我们之前曾报道，在AD背景下的小鼠中，DNA修复的丢失发展得更早和更严重的AD病理。在这些研究中，我们使用DNA聚合酶β(PolB)杂合子小鼠和3xTgAD模型制造3xTg/PolB(+/-)小鼠。PolB在碱基切除修复(BER)中发挥作用，BER是氧化应激的主要修复途径。我们的结果清楚地表明，DNA修复对于在衰老和病理条件下保存神经元功能是重要的。 NEIL1是一种重要的进化保守的DNA修复糖基酶，在脑内高表达。我们先前证明，NEIL1基因缺失的小鼠在空间记忆、嗅觉功能方面存在缺陷，对缺血再灌注损伤的保护作用较差。成人神经发生对神经可塑性和脑功能具有重要意义。然而，神经炎症是神经退行性疾病的常见特征，它可以促进或抑制神经发生。为了研究NEIL1在急性应激(伽马辐射IR)后的神经发生和神经炎症消退中可能起到的作用，我们使用了NEIL1基因缺失的小鼠。我们发现，它们减少了IR损伤后的神经再生和神经炎症的消退。IR治疗两周后，NEIL1基因缺失的小鼠仍然表现出应激反应受损。这些结果表明，DNA修复在神经发生中起着至关重要的作用，而且在DNA修复缺陷的动物中，急性应激后神经炎症的消退被推迟。这些发现对DNA修复能力不佳的人有影响，因为他们可能在创伤事件后遭受更大的伤害。

Our goal here is to determine whether changes in the formation or processing of oxidative DNA damage are associated with neurodegeneration and Alzheimers Disease (AD). It is our hypothesis that DNA repair systems play critical roles in responding to multiple types of acute and chronic cellular stress. We have identified a DNA damage response cascade leading from PARP1 to defected mitophagy. In the rare autosomal recessive disease Ataxia Telangiectasia (AT,) we documented increased PARylation, low NAD+ and mitochondrial dysfunction across multiple species. Importantly, treatment with NAD+ precursors that restored NAD levels reduced the severity of AT neuropathology, improved neuromuscular function, delayed memory loss and dramatically extended lifespan. Mechanistically, we ascribed the benefits to improvements in DNA repair and mitophagy. This work underscores the important linkage between DNA repair and mitochondrial function and further points to novel therapeutic interventions. We previously reported that loss of DNA repair in mice on an AD background develop earlier and more severe AD pathology. In those studies, we used DNA polymerase beta (PolB) heterozygous mice and the 3xTgAD model to make 3xTg/PolB(+/-) mice. PolB functions in base excision repair (BER) and BER is the primary repair pathway for oxidative stress. Our results have clearly shown that DNA repair is important for preserving neuronal function during aging and under pathological conditions. Neil1 is an important evolutionarily conserved DNA repair glycosylase that shows high expression in the brain. We previously demonstrated that Neil1-null mice had deficiencies in spatial memory, olfaction functions, and were less protected from ischemic reperfusion injury. Adult neurogenesis is important for neural plasticity and brain function. However, neuroinflammation is a common feature found in neurodegenerative disorders and neurogenesis can either be enhanced or inhibited by it. To investigate what role Neil1 may contribute to neurogenesis and neuroinflammation resolution after an acute stress (gamma irradiation IR), we used Neil1 null mice. We found that they have reduced neurogenesis and resolution of neuroinflammation following IR damage. Two weeks after IR treatment, Neil1-null mice still showed impaired stress responses. These results demonstrate that DNA repair plays a vital role in neurogenesis and further that the resolution of neuroinflammation following acute stress is delayed in DNA repair deficient animals. These findings have implications for individuals with suboptimal DNA repair capacities as they may suffer greater injury following traumatic events.