title: The metal transporter SMF-3/DMT-1 mediates aluminum-induced dopamine neuron degeneration.
abstract: Aluminum (Al(3+)) is the most prevalent metal in the earth's crust and is a known human neurotoxicant. Al(3+) has been shown to accumulate in the substantia nigra of patients with Parkinson's disease (PD), and epidemiological studies suggest correlations between Al(3+) exposure and the propensity to develop both PD and the amyloid plaque-associated disorder Alzheimer's disease (AD). Although Al(3+) exposures have been associated with the development of the most common neurodegenerative disorders, the molecular mechanism involved in Al(3+) transport in neurons and subsequent cellular death has remained elusive. In this study, we show that a brief exposure to Al(3+) decreases mitochondrial membrane potential and cellular ATP levels, and confers dopamine (DA) neuron degeneration in the genetically tractable nematode Caenorhabditis elegans (C. elegans). Al(3+) exposure also exacerbates DA neuronal death conferred by the human PD-associated protein α-synuclein. DA neurodegeneration is dependent on SMF-3, a homologue to the human divalent metal transporter (DMT-1), as a functional null mutation partially inhibits the cell death. We also show that SMF-3 is expressed in DA neurons, Al(3+) exposure results in a significant decrease in protein levels, and the neurodegeneration is partially dependent on the PD-associated transcription factor Nrf2/SKN-1 and caspase Apaf1/CED-4. Furthermore, we provide evidence that the deletion of SMF-3 confers Al(3+) resistance due to sequestration of Al(3+) into an intracellular compartment. This study describes a novel model for Al(3+)-induced DA neurodegeneration and provides the first molecular evidence of an animal Al(3+) transporter.
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: VanDuyn
authors.forename: Raja
authors.initials: R
authors.lastname: Settivari
authors.forename: Jennifer
authors.initials: J
authors.lastname: LeVora
authors.forename: Shaoyu
authors.initials: S
authors.lastname: Zhou
authors.forename: Jason
authors.initials: J
authors.lastname: Unrine
authors.forename: Richard
authors.initials: R
authors.lastname: Nass
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000535:Aluminum / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects*; D006801:Humans; D013058:Mass Spectrometry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology*; D014157:Transcription Factors / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D000255:Adenosine Triphosphate; D000535:Aluminum; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D000099236:Solute Carrier Family 11, Member 2; C089224:Ced-4 protein, C elegans; C548882:smf-3 protein, C elegans; C073702:skn-1 protein, C elegans