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SLC30A10 Mutation Involved in Parkinsonism Results in Manganese Accumulation within Nanovesicles of the Golgi Apparatus

Abstract : Manganese (Mn) is an essential metal that can be neurotoxic when elevated exposition occurs leading to parkinsonian-like syndromes. Mutations in the Slc30a10 gene have been identified in new forms of familial parkinsonism. SLC30A10 is a cell surface protein involved in the efflux of Mn and protects the cell against Mn toxicity. Disease-causing mutations block the efflux activity of SLC30A10, resulting in Mn accumulation. Determining the intracellular localization of Mn when disease-causing SLC30A10 mutants are expressed is essential to elucidate the mechanisms of Mn neurotoxicity. Here, using organelle fluorescence microscopy and synchrotron X-ray fluorescence (SXRF) imaging, we found that Mn accumulates in the Golgi apparatus of human cells transfected with the disease-causing SLC30A10-Δ105–107 mutant under physiological conditions and after exposure to Mn. In cells expressing the wild-type SLC30A10 protein, cellular Mn content was low after all exposure conditions, confirming efficient Mn efflux. In nontransfected cells that do not express endogenous SLC30A10 and in mock transfected cells, Mn was located in the Golgi apparatus, similarly to its distribution in cells expressing the mutant protein, confirming deficient Mn efflux. The newly developed SXRF cryogenic nanoimaging (<50 nm resolution) indicated that Mn was trapped in single vesicles within the Golgi apparatus. Our results confirm the role of SLC30A10 in Mn efflux and the accumulation of Mn in cells expressing the disease-causing SLC30A10-Δ105–107 mutation. Moreover, we identified suborganelle Golgi nanovesicles as the main compartment of Mn accumulation in SLC30A10 mutants, suggesting interactions with the vesicular trafficking machinery as a cause of the disease.
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Submitted on : Wednesday, February 13, 2019 - 2:54:25 AM
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Asuncion Carmona, Charles E. Zogzas, Stéphane Roudeau, Francesco Porcaro, Jan Garrevoet, et al.. SLC30A10 Mutation Involved in Parkinsonism Results in Manganese Accumulation within Nanovesicles of the Golgi Apparatus. ACS Chem.Neurosci., 2019, 10 (1), pp.599-609. ⟨10.1021/acschemneuro.8b00451⟩. ⟨hal-02017059⟩



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