The role of poly(ADP-ribose) polymerases in manganese exposed Caenorhabditis elegans

Catherine Neumann, Jessica Baesler, Gereon Steffen, Merle Marie Nicolai, Tabea Zubel, Michael Aschner, Alexander Bürkle, Aswin Mangerich, Tanja Schwerdtle, Julia Bornhorst

Research output: Contribution to journalArticle

Abstract

Background and aim: When exceeding the homeostatic range, manganese (Mn) might cause neurotoxicity, characteristic of the pathophysiology of several neurological diseases. Although the underlying mechanism of its neurotoxicity remains unclear, Mn-induced oxidative stress contributes to disease etiology. DNA damage caused by oxidative stress may further trigger dysregulation of DNA-damage-induced poly(ADP-ribosyl)ation (PARylation), which is of central importance especially for neuronal homeostasis. Accordingly, this study was designed to assess in the genetically traceable in vivo model Caenorhabditis elegans the role of PARylation as well as the consequences of loss of pme-1 or pme-2 (orthologues of PARP1 and PARP2) in Mn-induced toxicity. Methods: A specific and sensitive isotope-dilution liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed to quantify PARylation in worms. Next to monitoring the PAR level, pme-1 and pme-2 gene expression as well as Mn-induced oxidative stress was studied in wildtype worms and the pme deletion mutants. Results and conclusion: While Mn failed to induce PARylation in wildtype worms, toxic doses of Mn led to PAR-induction in pme-1-deficient worms, due to an increased gene expression of pme-2 in the pme-1 deletion mutants. However, this effect could not be observed at sub-toxic Mn doses as well as upon longer incubation times. Regarding Mn-induced oxidative stress, the deletion mutants did not show hypersensitivity. Taken together, this study characterizes worms to model PAR inhibition and addresses the consequences for Mn-induced oxidative stress in genetically manipulated worms.

Original languageEnglish (US)
Pages (from-to)21-27
Number of pages7
JournalJournal of Trace Elements in Medicine and Biology
Volume57
DOIs
Publication statusPublished - Jan 2020

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Keywords

  • Caenorhabditis elegans
  • DNA damage response
  • Manganese
  • Oxidative stress
  • Poly(ADP-ribosyl)ation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Inorganic Chemistry

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