The metal transporter SMF‐3/DMT‐1 mediates aluminum‐induced dopamine neuron degeneration. (21st November 2012)

• Record Type: Journal Article
• Authors: VanDuyn, Natalia; Settivari, Raja; LeVora, Jennifer; Zhou, Shaoyu; Unrine, Jason; Nass, Richard
• Is Part Of: Journal of neurochemistry. Volume 124:Number 1(2013:Jan.)
• Page Start: 147
• Page End: 157
• Publication Date: 2012-11-21
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.12072
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc12072-abs-0001"> <title>Abstract</title> <p>Aluminum (Al<sup>3+</sup>) is the most prevalent metal in the earth's crust and is a known human neurotoxicant. Al<sup>3+</sup> has been shown to accumulate in the substantia nigra of patients with Parkinson's disease (PD), and epidemiological studies suggest correlations between Al<sup>3+</sup> exposure and the propensity to develop both PD and the amyloid plaque‐associated disorder Alzheimer's disease (AD). Although Al<sup>3+</sup> exposures have been associated with the development of the most common neurodegenerative disorders, the molecular mechanism involved in Al<sup>3+</sup> transport in neurons and subsequent cellular death has remained elusive. In this study, we show that a brief exposure to Al<sup>3+</sup> decreases mitochondrial membrane potential and cellular ATP levels, and confers dopamine (DA) neuron degeneration in the genetically tractable nematode <italic>Caenorhabditis elegans</italic> (<italic>C. elegans</italic>). Al<sup>3+</sup> 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<sup>3+</sup> 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<sup>3+</sup> resistance due to sequestration of Al<sup>3+</sup> into an intracellular compartment. This study describes a novel model for Al<sup>3</sup><sup>+</sup>‐induced DA neurodegeneration and provides the first molecular evidence of an animal Al<sup>3+</sup> transporter.</p> </abstract>