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

67 Citations (Scopus)

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

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Dopaminergic Neurons
Caenorhabditis elegans
Neurons
Parkinson Disease
Dopamine
Metals
Synucleins
Manganese
Oxygen Consumption
Membrane Potentials
Glutathione
Vertebrates
Mitochondria
Epidemiologic Studies
Reactive Oxygen Species
Homeostasis
Head
Oxygen
Membranes
solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

The divalent metal transporter homologues SMF-1/2 mediate dopamine neuron sensitivity in Caenorhabditis elegans models of manganism and Parkinson disease. / Settivari, Raja; LeVora, Jennifer; Nass, Richard.

In: Journal of Biological Chemistry, Vol. 284, No. 51, 18.12.2009, p. 35758-35768.

Research output: Contribution to journalArticle

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