title: SLC30A10 is a cell surface-localized manganese efflux transporter, and parkinsonism-causing mutations block its intracellular trafficking and efflux activity.
abstract: Manganese (Mn) is an essential metal, but elevated cellular levels are toxic and may lead to the development of an irreversible parkinsonian-like syndrome that has no treatment. Mn-induced parkinsonism generally occurs as a result of exposure to elevated Mn levels in occupational or environmental settings. Additionally, patients with compromised liver function attributable to diseases, such as cirrhosis, fail to excrete Mn and may develop Mn-induced parkinsonism in the absence of exposure to elevated Mn. Recently, a new form of familial parkinsonism was reported to occur as a result of mutations in SLC30A10. The cellular function of SLC30A10 and the mechanisms by which mutations in this protein cause parkinsonism are unclear. Here, using a combination of mechanistic and functional studies in cell culture, Caenorhabditis elegans, and primary midbrain neurons, we show that SLC30A10 is a cell surface-localized Mn efflux transporter that reduces cellular Mn levels and protects against Mn-induced toxicity. Importantly, mutations in SLC30A10 that cause familial parkinsonism blocked the ability of the transporter to traffic to the cell surface and to mediate Mn efflux. Although expression of disease-causing SLC30A10 mutations were not deleterious by themselves, neurons and worms expressing these mutants exhibited enhanced sensitivity to Mn toxicity. 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 potential management of Mn-induced parkinsonism, including that occurring as a result of mutations in SLC30A10.
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, Institutes for Cellular and Molecular Biology and for Neuroscience, University of Texas at Austin, Austin, Texas 78701.
authors.forename: Dinorah
authors.initials: D
authors.lastname: Leyva-Illades
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, and.
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, Institutes for Cellular and Molecular Biology and for Neuroscience, University of Texas at Austin, Austin, Texas 78701.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Zogzas
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, Institutes for Cellular and Molecular Biology and for Neuroscience, University of Texas at Austin, Austin, Texas 78701.
authors.forename: Steven
authors.initials: S
authors.lastname: Hutchens
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, Institutes for Cellular and Molecular Biology and for Neuroscience, University of Texas at Austin, Austin, Texas 78701.
authors.forename: Jonathan M
authors.identifier: http://orcid.org/0000-0001-5440-1991
authors.initials: JM
authors.lastname: Mercado
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, Institutes for Cellular and Molecular Biology and for Neuroscience, University of Texas at Austin, Austin, Texas 78701.
authors.forename: Caleb D
authors.identifier: http://orcid.org/0000-0003-4900-4515
authors.initials: CD
authors.lastname: Swaim
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, Institutes for Cellular and Molecular Biology and for Neuroscience, University of Texas at Austin, Austin, Texas 78701.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morrisett
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-8552.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bowman
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, and michael.aschner@einstein.yu.edu som@austin.utexas.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, Institutes for Cellular and Molecular Biology and for Neuroscience, University of Texas at Austin, Austin, Texas 78701, michael.aschner@einstein.yu.edu som@austin.utexas.edu.
authors.forename: Somshuvra
authors.initials: S
authors.lastname: Mukhopadhyay
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D008345:Manganese / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D008345:Manganese
keywords: GPP130; SLC30A10; efflux; manganese; parkinsonism; trafficking