Novel DNA damage-Based Mechanisms and Therapeutics for Parkinson’s disease

帕金森氏病(PD)是一种常见的、毁灭性的神经退行性疾病，影响多达 美国有100万人，全球有1000万人或更多。目前，还没有治疗干预措施。 阻止或延缓帕金森病的进展。已经提出了几种假说作为帕金森病的起因， 包括多巴胺能神经元的丧失、线粒体功能障碍、氧化应激和α-突触核蛋白 沉积(路易小体)，但帕金森病的确切原因仍不清楚。最近的研究强调了 核DNA损伤，特别是核DNA双链断裂(DNA DSB)在 包括帕金森病在内的广泛人类神经退行性疾病中神经元丢失的进展。 然而，目前尚不清楚核DNA双链断裂是帕金森病的主要驱动因素，还是只是伴随出现 随着疾病的进展，以及2)增加了帕金森病发展的额外风险因素。虽然，DNA的一个作用 双链断裂在神经疾病中的研究相当深入，其参与神经退行性变的机制 帕金森病期间的行为缺陷是未知的。这代表着我们知识上的差距，这是 拟议的研究将涉及。为了确定DNADSB在帕金森病中的作用，我们产生并表征了一个 新颖的小鼠模型系统。我们之前已经证明了CDKN1A相互作用锌的缺乏 指蛋白1(CIZ1)是一种核蛋白，可导致辐射小鼠持续的DNA双链断裂和细胞死亡 胚胎成纤维细胞。老年CIZ1KO小鼠的大脑显示出明显和持续的DNA双链断裂，氧化 压力和细胞死亡，所有这些都存在于帕金森病中。此外，我们的初步发现表明， 帕金森病患者和帕金森病小鼠模型脑中DNA DSB升高和CIZ1水平降低。 我们的中心假设是，核DNA双链断裂在大脑中的积累增加有助于 帕金森病小鼠的神经变性和行为缺陷以及DNA修复在其中起关键作用 减轻帕金森病的病理后果。本应用程序的目标是1)了解 核DNA双链断裂在帕金森病发病机制中的作用及其与多巴胺能神经元丢失的关系 目的：探讨DNA修复激活剂对改善帕金森病后神经病理症状的疗效。我们 提出两个具体目标来检验我们的假设。在目标1中，我们将定义DNA的作用和机制 DSB在重述小鼠模型中神经退行性变和行为功能障碍进展中的作用 帕金森病的主要特征。在目标2中，我们将确定DNA修复激活剂的治疗益处，以有效地 抑制DNA损伤介导的帕金森病小鼠模型的神经退行性变和行为缺陷。我们的 预计将提出一项提案，以确定DNA DSB在帕金森病中的潜在贡献，并确定其治疗方法 靶向DNA损伤反应在减轻帕金森病病理后果方面的好处。

Parkinson’s disease (PD) is a common and devastating neurodegenerative disorder that affects up to one million individuals in the US and 10 million or more worldwide. Currently, there are no therapeutic interventions that stop or slow the progression of PD. Several hypotheses have been proposed as causative of PD, including, loss of dopaminergic neurons, mitochondrial dysfunction, oxidative stress, and α-synuclein deposition (Lewy bodies), but the exact causes of PD are still unclear. More recent studies have highlighted the role of nuclear DNA damage, particularly, nuclear DNA double-strand breaks (DNA DSBs), in the progression of neuronal loss in a broad spectrum of human neurodegenerative diseases including PD. However, it is not clear if nuclear DNA DSBs 1) serve as a primary driver of PD or simply occur concomitant with disease progression, and 2) confer an additional risk factor for PD development. Although, a role of DNA DSBs in neurological disorders is fairly-well studied, the mechanisms of its involvement in neurodegeneration and behavioral deficits during PD conditions are unknown. This represents a gap in our knowledge, which this proposed study will address. To define the role of DNA DSBs in PD, we have generated and characterized a novel mouse model system. We have previously demonstrated that a deficiency of CDKN1A-interacting zinc finger protein 1 (CIZ1), a nuclear protein, leads to sustained DNA DSBs, and cell death in irradiated mouse embryonic fibroblasts. The brains of aged CIZ1KO mice show overt and sustained DNA DSBs, oxidative stress, and cell death, all of which are found in PD. Furthermore, our preliminary findings demonstrated, elevated DNA DSBs and reduced CIZ1 levels in the brains of Parkinson’s patients and mouse model of PD. Our central hypothesis is that the increased accumulation of nuclear DNA DSBs in the brain contributes to neurodegeneration and behavioral deficits in Parkinsonian mice and that DNA repair plays a critical role in alleviating the pathological consequences in PD. The objectives of this application are 1) to understand the role of nuclear DNA DSBs in PD pathogenesis and how they relate to the loss of dopaminergic neurons and 2) to test the therapeutic benefits of DNA repair activators in alleviating post-PD neuropathological symptoms. We propose two specific aims to test our hypothesis. In Aim 1, we will define the role and mechanisms of DNA DSBs in the progression of neurodegeneration and behavioral dysfunction in a mouse model that recapitulates key features of PD. In Aim 2, we will determine the therapeutic benefits of DNA repair activators to effectively suppress DNA damage-mediated neurodegeneration and behavioral deficit in mouse models of PD. Our proposal is expected to identify the potential contribution of DNA DSBs in PD and determine the therapeutic benefits of targeting the DNA damage response in alleviating the pathological consequences in PD.