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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.
AuthorsNatalia VanDuyn, Raja Settivari, Jennifer LeVora, Shaoyu Zhou, Jason Unrine, Richard Nass
JournalJournal of neurochemistry (J Neurochem) Vol. 124 Issue 1 Pg. 147-57 (Jan 2013) ISSN: 1471-4159 [Electronic] England
PMID23106139 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Copyright© 2012 International Society for Neurochemistry.
Chemical References
  • Caenorhabditis elegans Proteins
  • Calcium-Binding Proteins
  • Cation Transport Proteins
  • Ced-4 protein, C elegans
  • DNA-Binding Proteins
  • SMF3 protein, C elegans
  • Transcription Factors
  • solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
  • skn-1 protein, C elegans
  • Adenosine Triphosphate
  • Aluminum
  • Tyrosine 3-Monooxygenase
Topics
  • Adenosine Triphosphate (metabolism)
  • Aluminum (toxicity)
  • Analysis of Variance
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins (genetics, metabolism, pharmacology)
  • Calcium-Binding Proteins (pharmacology)
  • Cation Transport Proteins (metabolism)
  • DNA-Binding Proteins (pharmacology)
  • Dopaminergic Neurons (drug effects)
  • Humans
  • Mass Spectrometry
  • Membrane Potential, Mitochondrial (drug effects, genetics)
  • Nerve Degeneration (chemically induced, pathology)
  • Transcription Factors (pharmacology)
  • Tyrosine 3-Monooxygenase (metabolism)

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