Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 51, Pages 35758-35768Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.051409
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Funding
- NIEHS [R011ES014459, R01ES010563]
- Dept. of Defense Manganese Health Research Program [W81XWH-05-1-0239]
- National Institutes of Health Center for Research Resources
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Parkinson disease (PD) and manganism are characterized by motor deficits and a loss of dopamine (DA) neurons in the substantia nigra pars compacta. Epidemiological studies indicate significant correlations between manganese exposure and the propensity to develop PD. The vertebrate divalent metal transporter-1 (DMT-1) contributes to maintaining cellular Mn2+ homeostasis and has recently been implicated in Fe2+-mediated neurodegeneration in PD. In this study we describe a novel model for manganism that incorporates the genetically tractable nematode Caenorhabditis elegans. We show that a brief exposure to Mn2+ increases reactive oxygen species and glutathione production, decreases oxygen consumption and head mitochondria membrane potential, and confers DA neuronal death. DA neurodegeneration is partially dependent on a putative homologue to DMT-1, SMF-1, as genetic knockdown or deletion partially inhibits the neuronal death. Mn2+ also amplifies the DA neurotoxicity of the PD-associated protein alpha-synuclein. Furthermore, both SMF-1 and SMF-2 are expressed in DA neurons and contribute to PD-associated neurotoxicant-induced DA neuron death. These studies describe a C. elegans model for manganism and show that DMT-1 homologues contribute to Mn2+- and PD-associated DA neuron vulnerability.
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