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

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.

• Authors: Tanara V Peres, Leticia P Arantes, Mahfuzur R Miah, Julia Bornhorst, Tanja Schwerdtle, Aaron B Bowman, Rodrigo B Leal, Michael Aschner
• Journal: Neurotoxicity research (Neurotox Res) Vol. 34 Issue 3 Pg. 584-596 (Oct 2018) ISSN: 1476-3524 [Electronic] United States
• PMID: 29882004 (Publication Type: Journal Article)

Chemical References

• Caenorhabditis elegans Proteins
• Chlorides
• Forkhead Transcription Factors
• Manganese Compounds
• daf-16 protein, C elegans
• Green Fluorescent Proteins
• Sod-3 protein, C elegans
• Superoxide Dismutase
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Sgk-1 protein, C elegans
• akt-2 protein, C elegans
• Glutathione
• manganese chloride
• Dopamine

Topics

• Active Transport, Cell Nucleus (drug effects, genetics)
• Animals
• Animals, Genetically Modified
• Behavior, Animal (physiology)
• Caenorhabditis elegans
• Caenorhabditis elegans Proteins (genetics, metabolism)
• Chlorides (toxicity)
• Disease Models, Animal
• Dopamine (metabolism)
• Forkhead Transcription Factors (metabolism)
• Glutathione (metabolism)
• Green Fluorescent Proteins (genetics, metabolism)
• Manganese Compounds
• Manganese Poisoning (complications, metabolism, pathology)
• Mutation (genetics)
• Nerve Degeneration (etiology, pathology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Signal Transduction (drug effects, physiology)
• Superoxide Dismutase (genetics, metabolism)