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

• Applicant: Professorin Dr. Julia Bornhorst
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine ; Food Chemistry
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 271720286

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.

• DFG Programme: Research Grants