期刊
NEUROTOXICITY RESEARCH
卷 34, 期 3, 页码 584-596出版社
SPRINGER
DOI: 10.1007/s12640-018-9915-1
关键词
Manganese . C. elegans; Signaling pathways; DAF-16; Akt/PKB; SGK-1
资金
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) Foundation
- Ministry of Education of Brazil [0407/13-5]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [202662/2014-4 - SWE]
- National Institute of Healt (NIH) [R01 ES10563]
- Deutsche Forschungsgemeinschaft (DFG) [Schw 903/9-1, BO 4103/2-1]
- NCI [P30CA013330]
- NIH Office of Research Infrastructure Programs [P40 OD010440]
- [R01 ES07331]
- [R01 ES020852]
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 1h 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 gamma-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.
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