The metal transporter SMF ‐3/ DMT ‐1 mediates aluminum‐induced dopamine neuron degeneration

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.