[
International Worm Meeting,
2015]
Environmental or occupational exposure to manganese (Mn) causes a neuropathy, resembling idiopathic Parkinson's disease (PD). In cells, high Mn levels can result in oxidative stress, mitochondrial dysfunction, protein aggregation and disruption of iron homeostasis. However, the mechanisms of Mn-induced neurotoxicity remain largely unknown. Recently, newly identified mutant alleles in human SLC30A10 have been found to cause Mn accumulation in the basal ganglia. Patients with mutations in SLC30A10 show symptoms of hepatic cirrhosis, dystonia, polycythemia and hypermanganesemia. Although clinical studies indicate the potential role of SLC30A10 in cellular Mn efflux, the exact function of this protein is unknown. Here, we present novel data on the role of SLC30A10 in C. elegans. We generated transgenic animals expressing either wildtype (WT) or mutant (L89P) SLC30A10. Expression of WT SLC30A10 increased survival rate upon Mn exposure. Whereas, expression in dopaminergic (DAergic) neurons attenuated Mn-induced DAergic neurodegeneration. In both cases mutant SLC30A10 showed no protection. Moreover, WT protein also improved DAergic neuron-specific behavior upon Mn exposure, while the mutant did not. In HeLa cells and GABAergic cells, only WT protein protected against Mn-induced cell death, consistent with our results in C. elegans. The Mn level was significantly lower in HeLa cells expressing WT SLC30A10. To explore why mutant SLC30A10 loses its Mn-protecting activity, transgenic worms were generated, expressing SLC30A10 with a C-terminal green fluorescent protein (GFP) tag. We found that WT SLC30A10 localized to the cell surface, while the mutant form accumulated in the endoplasmic reticulum (ER) and cytosol. Together, these results suggest that WT SLC30A10 protects cells from Mn-induced toxicity, while the mutant protein fails to do so, likely due to its failure to localize to the cell surface. Furthermore, SLC30A10 is likely a Mn-specific transporter although it was first posited to be a zinc transporter, as it did not protect from zinc-induced lethality in C. elegans. Our results provide novel insights into the mechanisms involved in the onset of a familial form of parkinsonism and highlight the possibility of using enhanced Mn efflux as a therapeutic strategy for the management of Mn-induced parkinsonism, including that occurring as a result of mutations in SLC30A10. (supported by National Institutes of Health Grants R01-ES010563 and R00-ES020488). .