The divalent metal transporter homologues SMF-1/2 mediate dopamine neuron sensitivity in Caenorhabditis elegans models of manganism and Parkinson disease

Raja Settivari, Jennifer LeVora, Richard Nass

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

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 α-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.

Original languageEnglish (US)
Pages (from-to)35758-35768
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number51
DOIs
StatePublished - Dec 18 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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