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Title: The divalent metal transporter homologues SMF-1/2 mediate dopamine neuron sensitivity in caenorhabditis elegans models of manganism and parkinson disease.

Authors: Settivari, Raja; Levora, Jennifer; Nass, Richard

Published In J Biol Chem, (2009 Dec 18)

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 Mn(2+) homeostasis and has recently been implicated in Fe(2+)-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 Mn(2+) 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. Mn(2+) 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 Mn(2+)- and PD-associated DA neuron vulnerability.

PubMed ID: 19801673 Exiting the NIEHS site

MeSH Terms: Animals; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/metabolism*; Caenorhabditis elegans/genetics; Caenorhabditis elegans/metabolism*; Cation Transport Proteins/genetics; Cation Transport Proteins/metabolism*; Cell Death; Disease Models, Animal; Dopamine/genetics; Dopamine/metabolism*; Humans; Iron/metabolism; Manganese Poisoning/genetics; Manganese Poisoning/metabolism*; Manganese/metabolism*; Manganese/toxicity; Neurons/metabolism*; Parkinson Disease/genetics; Parkinson Disease/metabolism*; Reactive Oxygen Species/metabolism; Sequence Homology, Amino Acid

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