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

Abstract

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). Al³⁺ 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 Al³⁺-induced DA neurodegeneration and provides the first molecular evidence of an animal Al³⁺ transporter.