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

Aluminum (Al³⁺) is the most prevalent metal in the earth's crust and is a known human neurotoxicant. Al³⁺ has been shown to accumulate in the substantia nigra of patients with Parkinson's disease (PD), and epidemiological studies suggest correlations between Al³⁺ exposure and the propensity to develop both PD and the amyloid plaque-associated disorder Alzheimer's disease (AD). Although Al³⁺ exposures have been associated with the development of the most common neurodegenerative disorders, the molecular mechanism involved in Al³⁺ transport in neurons and subsequent cellular death has remained elusive. In this study, we show that a brief exposure to Al³⁺ 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, Al³⁺ 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 Al³⁺ resistance due to sequestration of Al³⁺ 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 Al³⁺ transporter. Aluminum exposure is a risk factor for Parkinson's disease and Alzheimer's disease, yet the molecular basis for intracellular Al transport and neurotoxicity is poorly defined. We developed a novel model for aluminum-induced dopamine neuron degeneration and provide the first molecular evidence of an animal aluminum transporter. This novel genetic model should facilitate the identification of molecular pathways and potential therapeutic targets involved in Al-associated DA neuron degeneration. Graphical abstract designed by Richard Nass and Albert William.