SLC30A10 Mutation Involved in Parkinsonism ... - ACS Publications

Oct 1, 2018 - ... Murielle Salomé⊥ , Peter Cloetens⊥ , Somshuvra Mukhopadhyay§ , and Richard Ortega*†‡. † Chemical Imaging and Speciation, CENBG, ...
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SLC30A10 mutation involved in parkinsonism results in manganese accumulation within nano-vesicles of the Golgi apparatus Asuncion Carmona, Charles E Zogzas, Stephane Roudeau, Francesco Porcaro, Jan Garrevoet, Kathryn Spiers, Murielle Salome, Peter Cloetens, Somshuvra Mukhopadhyay, and Richard Ortega ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00451 • Publication Date (Web): 01 Oct 2018 Downloaded from http://pubs.acs.org on October 9, 2018

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ACS Chemical Neuroscience

SLC30A10 mutation involved in parkinsonism results in manganese accumulation within nanovesicles of the Golgi apparatus Asuncion Carmona1,2,*, Charles E. Zogzas3, Stéphane Roudeau1,2, Francesco Porcaro1,2, Jan Garrevoet4, Kathryn M. Spiers4, Murielle Salomé5, Peter Cloetens5, Somshuvra Mukhopadhyay3 and Richard Ortega1,2,*

1

Chemical Imaging and Speciation, CENBG, University of Bordeaux, UMR 5797, 33175 Gradignan, France 2

CNRS, IN2P3, CENBG, UMR 5797, 33175 Gradignan, France

3

Division of Pharmacology & Toxicology; Institute for Cellular & Molecular Biology and Institute for Neuroscience, University of Texas, 78712 Austin, USA.

4

Deutsches Elektronen Synchrotron DESY, Notkestr. 85, Hamburg, 22607, Germany

5

European Synchrotron Radiation Facility, Grenoble, France

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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 protecting 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-∆105-107 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 non-transfected 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 nano-imaging (