Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity

Tanara V. Peres, Leticia P. Arantes, Mahfuzur R. Miah, Julia Bornhorst, Tanja Schwerdtle, Aaron B. Bowman, Rodrigo B. Leal, Michael Aschner

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Excessive levels of the essential metal manganese (Mn) may cause a syndrome similar to Parkinson’s disease. The model organism Caenorhabditis elegans mimics some of Mn effects in mammals, including dopaminergic neurodegeneration, oxidative stress, and increased levels of AKT. The evolutionarily conserved insulin/insulin-like growth factor-1 signaling pathway (IIS) modulates worm longevity, metabolism, and antioxidant responses by antagonizing the transcription factors DAF-16/FOXO and SKN-1/Nrf-2. AKT-1, AKT-2, and SGK-1 act upstream of these transcription factors. To study the role of these proteins in C. elegans response to Mn intoxication, wild-type N2 and loss-of-function mutants were exposed to Mn (2.5 to 100 mM) for 1 h at the L1 larval stage. Strains with loss-of-function in akt-1, akt-2, and sgk-1 had higher resistance to Mn compared to N2 in the survival test. All strains tested accumulated Mn similarly, as shown by ICP-MS. DAF-16 nuclear translocation was observed by fluorescence microscopy in WT and loss-of-function strains exposed to Mn. qRT-PCR data indicate increased expression of γ-glutamyl cysteine synthetase (GCS-1) antioxidant enzyme in akt-1 mutants. The expression of sod-3 (superoxide dismutase homologue) was increased in the akt-1 mutant worms, independent of Mn treatment. However, dopaminergic neurons degenerated even in the more resistant strains. Dopaminergic function was evaluated with the basal slowing response behavioral test and dopaminergic neuron integrity was evaluated using worms expressing green fluorescent protein (GFP) under the dopamine transporter (DAT-1) promoter. These results suggest that AKT-1/2 and SGK-1 play a role in C. elegans response to Mn intoxication. However, tissue-specific responses may occur in dopaminergic neurons, contributing to degeneration.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalNeurotoxicity Research
DOIs
StateAccepted/In press - Jun 7 2018

Fingerprint

Caenorhabditis elegans
Manganese
Toxicity
Dopaminergic Neurons
Neurons
Transcription Factors
Antioxidants
Caenorhabditis elegans Proteins
Dopamine Plasma Membrane Transport Proteins
Mammals
Oxidative stress
Fluorescence microscopy
Somatomedins
Ligases
Green Fluorescent Proteins
Fluorescence Microscopy
Metabolism
Superoxide Dismutase
Cysteine
Parkinson Disease

Keywords

  • Akt/PKB
  • C. elegans
  • DAF-16
  • Manganese
  • SGK-1
  • Signaling pathways

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

Peres, T. V., Arantes, L. P., Miah, M. R., Bornhorst, J., Schwerdtle, T., Bowman, A. B., ... Aschner, M. (Accepted/In press). Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity. Neurotoxicity Research, 1-13. https://doi.org/10.1007/s12640-018-9915-1

Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity. / Peres, Tanara V.; Arantes, Leticia P.; Miah, Mahfuzur R.; Bornhorst, Julia; Schwerdtle, Tanja; Bowman, Aaron B.; Leal, Rodrigo B.; Aschner, Michael.

In: Neurotoxicity Research, 07.06.2018, p. 1-13.

Research output: Contribution to journalArticle

Peres, TV, Arantes, LP, Miah, MR, Bornhorst, J, Schwerdtle, T, Bowman, AB, Leal, RB & Aschner, M 2018, 'Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity', Neurotoxicity Research, pp. 1-13. https://doi.org/10.1007/s12640-018-9915-1
Peres TV, Arantes LP, Miah MR, Bornhorst J, Schwerdtle T, Bowman AB et al. Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity. Neurotoxicity Research. 2018 Jun 7;1-13. https://doi.org/10.1007/s12640-018-9915-1
Peres, Tanara V. ; Arantes, Leticia P. ; Miah, Mahfuzur R. ; Bornhorst, Julia ; Schwerdtle, Tanja ; Bowman, Aaron B. ; Leal, Rodrigo B. ; Aschner, Michael. / Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity. In: Neurotoxicity Research. 2018 ; pp. 1-13.
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