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Involvement of AAT transporters in methylmercury toxicity in Caenorhabditis elegans.

ABSTRACT: Methylmercury (MeHg) is a potent neurotoxin that enters mammalian cells as a conjugate with L-cysteine through L-type large neutral amino acid transporter, LAT1, by a molecular mimicry mechanism by structurally resembling L-methionine. Caenorhabditis elegans (C. elegans) has been increasingly used to study the neurotoxic effects of MeHg, but little is known about uptake and transport of MeHg in the worm. This study examined whether MeHg uptake through LAT1 is evolutionarily conserved in nematodes. MeHg toxicity in C. elegans was blocked by pre-treatment of worms with l-methionine, suggesting a role for amino acid transporters in MeHg transport. Knockdown of aat-1, aat-2, and aat-3, worm homologues to LAT1, increased the survival of C. elegans following MeHg treatment and significantly attenuated MeHg content following exposure. These results indicate that MeHg is transported in the worm by a conserved mechanism dependent on functioning amino acid transporters.

SUBMITTER: Caito SW

PROVIDER: S-EPMC3697847 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Involvement of AAT transporters in methylmercury toxicity in Caenorhabditis elegans.

Caito Samuel W SW Zhang Yaofang Y Aschner Michael M

Biochemical and biophysical research communications 20130510 4

Methylmercury (MeHg) is a potent neurotoxin that enters mammalian cells as a conjugate with L-cysteine through L-type large neutral amino acid transporter, LAT1, by a molecular mimicry mechanism by structurally resembling L-methionine. Caenorhabditis elegans (C. elegans) has been increasingly used to study the neurotoxic effects of MeHg, but little is known about uptake and transport of MeHg in the worm. This study examined whether MeHg uptake through LAT1 is evolutionarily conserved in nematode ...[more]

PMID: 23669041

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Project description:The neurotransmitter dopamine is a neuromodulator in the positive and negative regulation of brain circuits. Dopamine insufficiency or overload has been implicated in aberrant activities of neural circuits that play key roles in the pathogenesis of neurological and psychiatric diseases. Dopaminergic neurons are vulnerable to environmental insults. The neurotoxin methylmercury (MeHg) produces dopaminergic neuron damage in rodent as well as in Caenorhabditis elegans (C. elegans) models. Previous studies have demonstrated the utility of C. elegans as an alternative and complementary experimental model in dissecting out mechanism of MeHg-induced dopaminergic neurodegeneration. However, a sensitive pathological change that marks early events in neurodegeneration induced by environmental level of MeHg, is still lacking. By establishing a chronic exposure C. elegans model, for the first time, we have shown the propensity of MeHg (5 μM, 10 days) to induce bright puncta of dat-1::mCherry aggreagtes in the dendrites of cephalic (2 CEPs) dopaminergic neurons in a dose- and time-dependent manner, while these changes were not found in other dopaminergic neurons: anterior deirids (2 ADEs) and posterior deirids (2 PDEs), cholinergic neurons (2 AIYs) or glutamatergic neurons (2 PVDs). The bright puncta appear as an aggregation of mCherry proteins accumulating in dendrites. Further staining shows that the puncta were not inclusions in lysosome, or amyloid protein aggregates. In addition, features of the puncta including enlarged sphere shape (0.5-2 μm diameters), bright and accompanying with the shrinkage of the dendrite suggest that the puncta are likely composed of homologous mCherry molecules packaged at the dendritic site for exportation. Moreover, in the glutathione S-transferase 4 (gst-4) transcriptional reporter strain and RT-PCR assay, the expression levels of gst-4 and tubulins (tba-1 and tba-2) genes were not significantly modified under this chronic exposure paradigm, but gst-4 did show significant changes in an one day exposure paradigm. Collectively, these results suggest that CEP dopaminergic neurons are a sensitive target of MeHg, and the current exposure paradigm could be used as a model to investigate mechanism of dopaminergic neurotoxicity.

Dataset Information

Involvement of AAT transporters in methylmercury toxicity in Caenorhabditis elegans.

Publications

Involvement of AAT transporters in methylmercury toxicity in Caenorhabditis elegans.

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