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  - Peres, Tanara V.
A1  - Eyng, Helena
A1  - Lopes, Samantha C.
A1  - Colle, Dirleise
A1  - Goncalves, Filipe M.
A1  - Venske, Debora K. R.
A1  - Lopes, Mark W.
A1  - Ben, Juliana
A1  - Bornhorst, Julia
A1  - Schwerdtle, Tanja
A1  - Aschner, Michael A.
A1  - Farina, Marcelo
A1  - Prediger, Rui D.
A1  - Leal, Rodrigo B.
T1  - Developmental exposure to manganese induces lasting motor and cognitive impairment in rats
JF  - Neurotoxicology : the interdisciplinary journal of effects to toxic substances on the nervous system
N2  - Exposure to high manganese (Mn) levels may damage the basal ganglia, leading to a syndrome analogous to Parkinson's disease, with motor and cognitive impairments. The molecular mechanisms underlying Mn neurotoxicity, particularly during development, still deserve further investigation. Herein, we addressed whether early-life Mn exposure affects motor coordination and cognitive function in adulthood and potential underlying mechanisms. Male Wistar rats were exposed intraperitoneally to saline (control) or MnCl2 (5, 10 or 20 mg/kg/day) from post-natal day (PND) 8-12. Behavioral tests were performed on PND 60-65 and biochemical analysis in the striatum and hippocampus were performed on PND14 or PND70. Rats exposed to Mn (10 and 20 mg/kg) performed significantly worse on the rotarod test than controls indicating motor coordination and balance impairments. The object and social recognition tasks were used to evaluate short-term memory. Rats exposed to the highest Mn dose failed to recognize a familiar object when replaced by a novel object as well as to recognize a familiar juvenile rat after a short period of time. However, Mn did not alter olfactory discrimination ability. In addition, Mn-treated rats displayed decreased levels of non-protein thiols (e.g. glutathione) and increased levels of glial fibrillary acidic protein (GFAP) in the striatum. Moreover, Mn significantly increased hippocampal glutathione peroxidase (GPx) activity. These findings demonstrate that acute low-level exposure to Mn during a critical neurodevelopmental period causes cognitive and motor dysfunctions that last into adulthood, that are accompanied by alterations in antioxidant defense system in both the hippocampus and striatum. (C) 2015 Elsevier Inc. All rights reserved.
KW  - Manganese
KW  - Neurotoxicity
KW  - Development
KW  - Motor coordination
KW  - Cognition
Y1  - 2015
U6  - https://doi.org/10.1016/j.neuro.2015.07.005
SN  - 0161-813X
SN  - 1872-9711
VL  - 50
SP  - 28
EP  - 37
PB  - Elsevier
CY  - Amsterdam
ER  -