TY - JOUR
T1 - The role of poly(ADP-ribose) polymerases in manganese exposed Caenorhabditis elegans
AU - Neumann, Catherine
AU - Baesler, Jessica
AU - Steffen, Gereon
AU - Nicolai, Merle Marie
AU - Zubel, Tabea
AU - Aschner, Michael
AU - Bürkle, Alexander
AU - Mangerich, Aswin
AU - Schwerdtle, Tanja
AU - Bornhorst, Julia
N1 - Funding Information:
We thank the German Research Foundation (DFG) for the financial support of BO 4103/2-1 , INST 38/537-1 , as well as the DFG Research Unit TraceAge ( FOR 2558 ) and the Konstanz Research School Chemical Biology (KoRS-CB, GSC 218 ). We thank for the European Regional Development Fund (EFRE). We would also like to thank the Caenorhabditis Genetics Center (CGC), which is funded by the NIH Office of Research Infrastructure Programs ( P40 OD010440 ), for providing the C. elegans strains used in this work. MA was supported in part by grants from the National Institute of Environmental Health Sciences (NIEHS) , R01 ES10563 R01 ES07331 .
Publisher Copyright:
© 2019
PY - 2020/1
Y1 - 2020/1
N2 - 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.
AB - 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.
KW - Caenorhabditis elegans
KW - DNA damage response
KW - Manganese
KW - Oxidative stress
KW - Poly(ADP-ribosyl)ation
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U2 - 10.1016/j.jtemb.2019.09.001
DO - 10.1016/j.jtemb.2019.09.001
M3 - Article
C2 - 31546209
AN - SCOPUS:85072301860
VL - 57
SP - 21
EP - 27
JO - Journal of Trace Elements in Medicine and Biology
JF - Journal of Trace Elements in Medicine and Biology
SN - 0946-672X
ER -