The role of SMF 1, SMF-2, SMF-3 in metal-induced whole animal vulnerability and dopamine neuron degeneration in Caenorhabditis elegans

Abstract

The etiology of many neurodegenerative diseases is unknown, but a number of studies indicate that a combination of both genetic and environmental factors contribute to the progression of disease. Exposure to environmental metals, such as Mn2+, Fe2+, Cu2+, and Al3+, has been shown to increase cell death that is characteristic of neurodegenerative disorders such as AD, PD, Wilson’s disease and Menkes disease. These metals are important in numerous biological processes in the brain and their homeostasis is regulated through multiple mechanisms of transport, storage, and secretion. The vertebrate divalent metal transporter-1 (DMT-1) has been implicated in transport and homeostasis of these divalent cations. In these studies I utilize Caenorhabditis elegans (C. elegans) to show that long term exposure to Mn2+ decreases animal viability in a dose-dependent manner, and I demonstrate that C. elegans homologues to DMT-1, SMF-1, SMF-2, and SMF-3, play specific roles in divalent metal ion-induced DA neurodegeneration. I show that SMF-1 contributes to Fe2+-induced DA neuron degeneration, SMF-3 contributes to Al3+-induced DA neuron degeneration, and both SMF-2 and DAT-1 contribute to Cu2+-induced DA neuron cell death. These studies utilize C. elegans as a powerful model to characterize molecules and pathways involved in metal toxicity and metal-induced DA neuron degeneration.