Manganese (Mn) is an essential metal but elevated levels are cytotoxic. Occupational and environmental exposure to elevated Mn lead to the development of an irreversible parkinsonian syndrome. Despite the clinical significance, mechanisms that regulate Mn homeostasis and detoxification are poorly understood and this has hindered therapeutic progress. An important advance in understanding how homeostatic control of Mn is maintained came from the recent discovery that mutations in the gene coding for SLC30A10 cause a familial form of Mn-induced Parkinsonism. The function of SLC30A10 in higher eukaryotes is ill-defined but, within the last year, we discovered that SLC30A10 was a cell surface localized Mn efflux transporter. Further, we tested several disease-causing mutants and observed that these mutants failed to traffic to the cell surface and also failed to mediate Mn efflux. Our results highlight the significance of SLC30A10 in regulating cellular Mn levels and begin to provide an explanation for the onset of Mn-induced Parkinsonism in individuals carrying mutations in SLC30A10. Based on the above results and the prior genetic studies, we hypothesize that SLC30A10 is the primary efflux transporter responsible for maintaining Mn levels and mediating Mn detoxification at the cellular and organismal level. Our hypothesis is supported by the fact that mutations in the other Mn efflux transporters do not cause Mn toxicity. Our goal is to test the above hypothesis and secure a comprehensive understanding of the regulation of Mn homeostasis and detoxification by SLC30A10 and Mn efflux. The mechanisms by which SLC30A10 mediates Mn transport and Mn regulates SLC30A10 function are unknown.
In Aim 1, we will elucidate these mechanisms and, in a set of clinically important studies, also test if chemical chaperones can rescue the trafficking and function of disease-causing SLC30A10 mutants.
In Aim 2, we will use a combination of assays in cell culture and genetically-modified mice to directly test our hypothesis that SLC30A10 is the primary transporter that mediates Mn detoxification. The mouse studies include assays to determine the functional consequences of altered SLC30A10 activity and Mn efflux against the neurotoxic effects of Mn in vivo and are translationally significant. Proposed studies will provide novel insights into the biology of SLC30A10 and enable us to better understand the role of this transporter in Mn homeostasis and induced Parkinsonism. Further, these studies will aid efforts to address important disease-related issues such as identifying polymorphisms in SLC30A10 that may alter the risk of Mn neurotoxicity in the general population, and also contribute to the development of innovative new treatments for the management of Mn-induced Parkinsonism.
Manganese is an occupational and environmental toxin that causes an irreversible parkinsonian syndrome. This grant application will determine the process by which Mn is removed from human cells. These studies will lay the foundation for developing drugs that can treat Mn-induced Parkinsonism by increasing the removal of Mn from cells.
