The divalent metal transporter homologues SMF-1/2 mediate dopamine neuron sensitivity in caenorhabditis elegans models of manganism and parkinson disease.
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.
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Raja
R
Settivari
Jennifer
J
Levora
Richard
R
Nass
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D004195:Disease Models, Animal; D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism; D008345:Manganese / Q000378:metabolism* / Q000633:toxicity; D020149:Manganese Poisoning / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D000099236:Solute Carrier Family 11, Member 2
D029742:Caenorhabditis elegans Proteins; D027682:Cation Transport Proteins; D004298:Dopamine; D007501:Iron; D008345:Manganese; D017382:Reactive Oxygen Species; D000099236:Solute Carrier Family 11, Member 2