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

• Published in: Neurotoxicity research Vol. 34; no. 3; pp. 584 - 596
• Main Authors: Peres, Tanara V., Arantes, Leticia P., Miah, Mahfuzur R., Bornhorst, Julia, Schwerdtle, Tanja, Bowman, Aaron B., Leal, Rodrigo B., Aschner, Michael
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2018
• Subjects: Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - genetics; Animals; Animals, Genetically Modified; Behavior, Animal - physiology; Biomedical and Life Sciences; Biomedicine; Caenorhabditis elegans; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cell Biology; Chlorides - toxicity; Disease Models, Animal; Dopamine - metabolism; Forkhead Transcription Factors - metabolism; Glutathione - metabolism; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Manganese Compounds; Manganese Poisoning - complications; Manganese Poisoning - metabolism; Manganese Poisoning - pathology; Mutation - genetics; Nerve Degeneration - etiology; Nerve Degeneration - pathology; Neurobiology; Neurochemistry; Neurology; Neurosciences; Original Article; Pharmacology/Toxicology; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Signaling pathways; SGK-1; Akt/PKB; DAF-16; Manganese; C. elegans
• ISSN: 1029-8428; 1476-3524
• DOI: 10.1007/s12640-018-9915-1

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.