TY  - JOUR
A1  - Peres, Tanara Vieira
A1  - Arantes, Leticia P.
A1  - Miah, Mahfuzur R.
A1  - Bornhorst, Julia
A1  - Schwerdtle, Tanja
A1  - Bowman, Aaron B.
A1  - Leal, Rodrigo B.
A1  - Aschner, Michael
T1  - Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity
JF  - Neurotoxicity Research
N2  - 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.
KW  - Manganese . C. elegans
KW  - Signaling pathways
KW  - DAF-16
KW  - Akt/PKB
KW  - SGK-1
Y1  - 2018
U6  - https://doi.org/10.1007/s12640-018-9915-1
SN  - 1029-8428
SN  - 1476-3524
VL  - 34
IS  - 3
SP  - 584
EP  - 596
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Ruszkiewicz, Joanna A.
A1  - de Macedo, Gabriel Teixeira
A1  - Miranda-Vizuete, Antonio
A1  - Teixeira da Rocha, Joao B.
A1  - Bowman, Aaron B.
A1  - Bornhorst, Julia
A1  - Schwerdtle, Tanja
A1  - Aschner, Michael
T1  - The cytoplasmic thioredoxin system in Caenorhabditis elegans affords protection from methylmercury in an age-specific manner
JF  - Neurotoxicology : the interdisciplinary journal of effects to toxic substances on the nervous system
N2  - Methylmercury (MeHg) is an environmental pollutant linked to many neurological defects, especially in developing individuals. The thioredoxin (TRX) system is a key redox regulator affected by MeHg toxicity, however the mechanisms and consequences of MeHg-induced dysfunction are not completely understood. This study evaluated the role of the TRX system in C. elegans susceptibility to MeHg during development. Worms lacking or overexpressing proteins from the TRX family were exposed to MeHg for 1 h at different developmental stage: L1, L4 and adult. Worms without cytoplasmic thioredoxin system exhibited age-specific susceptibility to MeHg when compared to wild-type (wt). This susceptibility corresponded partially to decreased total glutathione (GSH) levels and enhanced degeneration of dopaminergic neurons. In contrast, the overexpression of the cytoplasmic system TRX-1/TRXR-1 did not provide substantial protection against MeHg. Moreover, transgenic worms exhibited decreased protein expression for cytoplasmic thioredoxin reductase (TRXR-1). Both mitochondrial thioredoxin system TRX-2/TRXR-2, as well as other thioredoxin-like proteins: TRX-3, TRX-4, TRX-5 did not show significant role in C. elegans resistance to MeHg. Based on the current findings, the cytoplasmic thioredoxin system TRX-1/TRXR-1 emerges as an important age-sensitive protectant against MeHg toxicity in C. elegans.
KW  - Methylmercury
KW  - Age
KW  - Development
KW  - C. elegans
KW  - Thioredoxin
KW  - Thioredoxin reductase
Y1  - 2018
U6  - https://doi.org/10.1016/j.neuro.2018.08.007
SN  - 0161-813X
SN  - 1872-9711
VL  - 68
SP  - 189
EP  - 202
PB  - Elsevier
CY  - Amsterdam
ER  -