Role of DNA damage response in Mn-induced neurotoxicity in C. elegans

DNA 损伤反应在锰诱导的秀丽隐杆线虫神经毒性中的作用

• 批准号: 271720286
• 负责人: Professorin Dr. Julia Bornhorst
• 金额: --
• 依托单位: Arbeitsgruppe Lebensmittelchemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/271720286?language=en
• 关键词: Role; DNA; damage; response; Mn

Manganese (Mn) is an essential trace element occupying important physiological functions for human health. However, environmental or occupational overexposure may result in an irreversible condition known as manganism that shares similar neuropathology with Parkinson disease (PD), with overt dopaminergic (DAergic) cell loss associated with the presentation of motor and cognitive deficits. Although the underlying mechanism remains unclear, recently we identified the DNA damage related signaling reaction poly(ADP-ribosyl)ation to be highly sensitive to in vitro Mn exposure. A defective response to DNA damage has been shown to play a role in the etiology of a host of neurological disorders, including Parkinson disease, emphasizing the importance of DNA repair in neural homeostasis. Accordingly, this study is designed to assess the role of the DNA damage response in Mn-induced neurotoxicity with a special focus on interactions of DNA response genes and Mn using the in vivo model organism Caenorhabditis elegans (C. elegans). The first part of the project studies will determine if Mn-induced toxicity is exacerbated in DNA damage response (pme-1, pme-2, pme-3, pme-4 (C. elegans orthologs of human PARPs)) deletion mutants. Toxicity endpoints will include lethality, cellular stress and DNA damage, while in parallel the Mn content and the impact on other metal homeostasis e.g. Fe, Cu, Zn and Ca will be assessed to link the observed effects with physiologically relevant concentrations. Correlating dopaminergic (DAergic) neurodegeneration, DAergic signaling and function with DNA damage response related signaling following Mn exposure will provide novel insights in understanding Mn-induced neurotoxicity. Additionally, the interaction of the DNA damage response gene pme-1 with genes of various repair pathways is poorly understood. Studies on selected DNA repair genes will be carried out in the background of a loss-of-function pme-1 and in the presence of Mn to guide future studies on the most relevant pathways that are involved in Mn-induced neurotoxicity. Moreover, it will be investigated whether Mn exposure is inhibiting DNA damage response in wildtype worms as well as transgenic mutants of genes related to pme-1 (e.g. sirtuins, pink1, alpha-synuclein). To further identify novel targets of Mn-induced toxicity GABAergic neurodegeneration and the effect on MAPK signaling in the pme-1 deletion mutants will be studied. Identifying novel underlying mechanisms of Mn-induced neurotoxicity will provide novel targets for therapy strategies and may lay the foundation to identify neuroprotective strategies including neuroprotective properties of food constituents against Mn-induced neurotoxicity.

锰是人体必需的微量元素，对人体健康具有重要的生理功能。然而，环境或职业过度暴露可能导致称为锰中毒的不可逆病症，其与帕金森病（PD）具有相似的神经病理学，与运动和认知缺陷的表现相关的明显多巴胺能（DA能）细胞损失。虽然潜在的机制仍不清楚，最近我们确定了DNA损伤相关的信号反应聚（ADP-核糖基）化是高度敏感的体外锰暴露。对DNA损伤的缺陷反应已被证明在许多神经系统疾病（包括帕金森病）的病因学中起作用，强调了DNA修复在神经稳态中的重要性。因此，本研究旨在评估DNA损伤反应在锰诱导的神经毒性中的作用，特别关注DNA反应基因与锰的相互作用，使用体内模式生物秀丽隐杆线虫（C. elegans）。项目研究的第一部分将确定锰诱导的毒性是否在DNA损伤反应中加剧（pme-1，pme-2，pme-3，pme-4（C.人PARP的elegans直系同源物））缺失突变体。毒性终点将包括致死率、细胞应激和DNA损伤，同时将评估Mn含量和对其他金属稳态（如Fe、Cu、Zn和Ca）的影响，以将观察到的效应与生理相关浓度联系起来。锰暴露后多巴胺能（DA能）神经变性、DA能信号传导和功能与DNA损伤反应相关信号传导的相关性将为理解锰诱导的神经毒性提供新的见解。此外，DNA损伤反应基因pme-1与各种修复途径基因的相互作用知之甚少。选定的DNA修复基因的研究将在功能丧失的pme-1的背景下进行，并在锰的存在下，以指导未来的研究锰诱导的神经毒性中涉及的最相关的途径。此外，将研究Mn暴露是否抑制野生型蠕虫以及与pme-1相关的基因（例如sirtuins、pink 1、α-突触核蛋白）的转基因突变体的DNA损伤反应。为了进一步鉴定Mn诱导的毒性的新靶点，将研究pme-1缺失突变体中GABA能神经变性和对MAPK信号传导的影响。确定锰诱导的神经毒性的新的潜在机制将提供新的治疗策略的目标，并可能奠定基础，以确定神经保护策略，包括对锰诱导的神经毒性的食品成分的神经保护特性。

项目成果

Formation of trans-epoxy fatty acids correlates with formation of isoprostanes and could serve as biomarker of oxidative stress.

反式环氧脂肪酸的形成与异前列腺素的形成相关，并且可以作为氧化应激的生物标志物

• DOI: 10.1016/j.prostaglandins.2019.04.004
• 发表时间: 2019
• 期刊: Prostaglandins & other lipid mediators
• 影响因子: 2.9
• 作者: K. M. Rund;D. Heylmann;N. Seiwert;S. Wecklein;C. Oger;J. M. Galano;T. Durand;R. Chen;F. Gueler;J. Fahrer;J. Bornhorst;N. H. Schebb
• 通讯作者: N. H. Schebb