Journal of Drug Metabolism & Toxicology
Open Access

The role of a novel genetic factor (SLC30A10) in manganese-induced toxicity in C. Elegans

International Conference on Toxicogenomics and Drug Monitoring

August 25-27, 2015 Valencia, Spain

Michael Aschner1, Aaron B Bowman2 and Pan Chen1

1Albert Einstein College of Medicine, USA 2Vanderbilt University Medical Center, USA

Posters-Accepted Abstracts: J Drug Metab Toxicol

Abstract :

Environmental or occupational exposure to manganese (Mn) causes a neuropathy resembling idiopathic Parkinson��?s disease (PD). Exposure to excessive Mn levels has been linked to mitochondrial dysfunction, oxidative stress, protein aggregation and disruption of iron homeostasis. However, the mechanisms that mediate these impairments remain largely unknown, partially due to limited knowledge about Mn transporters. Recently, newly identified mutant alleles in human SLC30A10 have been found to cause Mn accumulation in the basal ganglia (Tuschl et al., 2012, Stamelou et al., 2012). Patients with the autosomal recessive mutations in SLC30A10 show symptoms of hepatic cirrhosis, dystonia, polycythemia and hypermanganesemia. Although clinical studies indicate the potential role of SLC30A10 in cellular efflux, the exact function of this protein has yet to be elucidated. Here, we present novel data on the role of SLC30A10 in C. elegans. A blast search found 5 potential SLC30A10 homologs in worms: CDF-1, CDF-2, Y105E8A.3, TTM-1 and TOC-1.CDF-1 shares the highest sequence identity to human SLC30A10 (~ 34%) and TOC-1 the lowest (~ 23%). Knock down of these genes (cdf-1, cdf-2, ttm-1 and toc-1) resulted in no change (cdf-2) or an increase (cdf-1, ttm-1 and toc-1) in survival after Mn treatment, indicating the worm homolog might function differently. Transgenic animals were generated expressing either WT or mutant SLC30A10 in different tissues of the worm. Somatic tissue expression (under sur-5 promoter) of WT SLC30A10 increases survival rate after Mn exposure; whereas expression in DAergic neurons attenuates their Mn-induced neurodegeneration. In both tissuesmutant SLC30A10 has no significant effect on Mn toxicity. To explore why mutant SLC30A10 loses its Mn-protection activity, we made a transgenic C-terminal tagged Green Fluorescent Protein (GFP) SLC30A10 fusion protein in C. elegans. Our results showed that mutant SLC30A10 fails to localize to the cell surface, like the WT form, and instead accumulated in the cytosol of both DAergic neurons and body wall muscle cells. All together, these results suggest that the activity of human SLC30A10 is not masked by the worm homologs, WT SLC30A10 protects cells from Mn toxicity and the mutant protein loses this activity, possibly due to failed surface expression.