Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity
- 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 strainsExcessive 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.…
Author details: | Tanara Vieira PeresORCiD, Leticia P. Arantes, Mahfuzur R. Miah, Julia BornhorstORCiDGND, Tanja SchwerdtleORCiDGND, Aaron B. Bowman, Rodrigo B. Leal, Michael AschnerORCiDGND |
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DOI: | https://doi.org/10.1007/s12640-018-9915-1 |
ISSN: | 1029-8428 |
ISSN: | 1476-3524 |
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/29882004 |
Title of parent work (English): | Neurotoxicity Research |
Publisher: | Springer |
Place of publishing: | New York |
Publication type: | Article |
Language: | English |
Date of first publication: | 2018/06/07 |
Publication year: | 2018 |
Release date: | 2021/09/22 |
Tag: | Akt/PKB; DAF-16; Manganese . C. elegans; SGK-1; Signaling pathways |
Volume: | 34 |
Issue: | 3 |
Number of pages: | 13 |
First page: | 584 |
Last Page: | 596 |
Funding institution: | Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) FoundationCAPES; Ministry of Education of Brazil [0407/13-5]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)National Council for Scientific and Technological Development (CNPq) [202662/2014-4 - SWE]; National Institute of Healt (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 ES10563]; "Deutsche Forschungsgemeinschaft" (DFG)German Research Foundation (DFG) [Schw 903/9-1, BO 4103/2-1]; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA013330]; NIH Office of Research Infrastructure Programs [P40 OD010440]; [R01 ES07331]; [R01 ES020852] |
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
DDC classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Peer review: | Referiert |
Publishing method: | Open Access / Green Open-Access |