41. Brouillet EP, Shinobu L, McGarvey U, Hochberg F, Beal MF (1993) Manganese injection into the rat striatum produces excitotoxic lesions by impairing energy metabolism. Exp Neurol 120: 89–94. 42. Loschmann PA, Lange KW, Wachtel H, Turski L (1994) MPTP-induced degeneration: interference with glutamatergic toxicity. J Neural Transm Suppl 43: 133–143. 43. Chun HS, Gibson GE, DeGiorgio LA, Zhang H, Kidd VJ, et al. (2001) Dopaminergic cell death induced by MPP(+), oxidant and specific neurotox- icants shares the common molecular mechanism. J Neurochem 76: 1010–1021. 44. Suzuki Y, Mouri T, Suzuki Y, Nishiyama K, Fujii N (1975) Study of subacute toxicity of manganese dioxide in monkeys. Tokushima J Exp Med 22: 5–10. 45. HaMai D, Bondy SC (2004) Oxidative basis of manganese neurotoxicity. Ann N Y Acad Sci 1012: 129–141. 46. Migheli R, Godani C, Sciola L, Delogu MR, Serra PA, et al. (1999) Enhancing effect of manganese on L-DOPA-induced apoptosis in PC12 cells: role of oxidative stress. J Neurochem 73: 1155–1163. 47. Parenti M, Rusconi L, Cappabianca V, Parati EA, Groppetti A (1988) Role of dopamine in manganese neurotoxicity. Brain Res 473: 236–240. 48. Tomas-Camardiel M, Herrera AJ, Venero JL, Cruz Sanchez-Hidalgo M, Cano J, et al. (2002) Differential regulation of glutamic acid decarboxylase mRNA and tyrosine hydroxylase mRNA expression in the aged manganese- treated rats. Brain Res Mol Brain Res 103: 116–129. 49. Hsu LJ, Sagara Y, Arroyo A, Rockenstein E, Sisk A, et al. (2000) alpha- synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol 157: 401–410. 50. Sherer TB, Betarbet R, Stout AK, Lund S, Baptista M, et al. (2002) An in vitro model of Parkinson’s disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. J Neurosci 22: 7006–7015. 51. Tanaka Y, Engelender S, Igarashi S, Rao RK, Wanner T, et al. (2001) Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum Mol Genet 10: 919–926. 52. Witholt R, Gwiazda RH, Smith DR (2000) The neurobehavioral effects of subchronic manganese exposure in the presence and absence of pre- parkinsonism. Neurotoxicol Teratol 22: 851–861. 53. Kuwahara T, Koyama A, Gengyo-Ando K, Masuda M, Kowa H, et al. (2006) Familial Parkinson mutant alpha-synuclein causes dopamine neuron dysfunc- tion in transgenic Caenorhabditis elegans. J Biol Chem 281: 334–340. 54. Braungart E, Gerlach M, Riederer P, Baumeister R, Hoener MC (2004) Caenorhabditis elegans MPP+ model of Parkinson’s disease for high- throughput drug screenings. Neurodegener Dis 1: 175–183. 55. Lakso M, Vartiainen S, Moilanen AM, Sirvio J, Thomas JH, et al. (2003) Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human alpha-synuclein. J Neurochem 86: 165–172. 56. Nass R, Hall DH, Miller DM, 3rd, Blakely RD (2002) Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans. Proc Natl Acad Sci U S A 99: 3264–3269. 57. Locke CJ, Fox SA, Caldwell GA, Caldwell KA (2008) Acetaminophen attenuates dopamine neuron degeneration in animal models of Parkinson’s disease. Neurosci Lett 439: 129–133. 58. Wang YM, Pu P, Le WD (2007) ATP depletion is the major cause of MPP+ induced dopamine neuronal death and worm lethality in alpha-synuclein transgenic C. elegans. Neurosci Bull 23: 329–335. 59. Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, et al. (2009) Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet 41: 308–315. 60. van Ham TJ, Thijssen KL, Breitling R, Hofstra RM, Plasterk RH, et al. (2008) C. elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during aging. PLoS Genet 4: e1000027. doi:10.1371/journal.p- gen.1000027. 61. Kuwahara T, Koyama A, Koyama S, Yoshina S, Ren CH, et al. (2008) A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in alpha-synuclein transgenic C. elegans. Hum Mol Genet 17: 2997–3009. 62. Ichibangase T, Saimaru H, Takamura N, Kuwahara T, Koyama A, et al. (2008) Proteomics of Caenorhabditis elegans over-expressing human alpha- synuclein analyzed by fluorogenic derivatization-liquid chromatography/ tandem mass spectrometry: identification of actin and several ribosomal proteins as negative markers at early Parkinson’s disease stages. Biomed Chromatogr 22: 232–234. 63. Cao S, Gelwix CC, Caldwell KA, Caldwell GA (2005) Torsin-mediated protection from cellular stress in the dopaminergic neurons of Caenorhabditis elegans. J Neurosci 25: 3801–3812. 64. Hamamichi S, Rivas RN, Knight AL, Cao S, Caldwell KA, et al. (2008) Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson’s disease model. Proc Natl Acad Sci U S A 105: 728–733. 65. Settivari R, Levora J, Nass R (2009) The divalent metal transporter homologues SMF-1/2 mediates dopamine neuron sensitivity in caenorhabditis elegans models of manganism and Parkinson’s disease. J Biol Chem. 66. Au C, Benedetto A, Anderson J, Labrousse A, Erikson K, et al. (2009) SMF-1, SMF-2 and SMF-3 DMT1 orthologues regulate and are regulated differentially by manganese levels in C. elegans. PLoS ONE 4: e7792. doi:10.1371/ journal.pone.0007792. BLI-3/Dopamine-Dependent Mn-Induced Neurotoxicity 67. Cass WA, Zahniser NR, Flach KA, Gerhardt GA (1993) Clearance of exogenous dopamine in rat dorsal striatum and nucleus accumbens: role of metabolism and effects of locally applied uptake inhibitors. J Neurochem 61: 2269–2278. 68. Kilty JE, Lorang D, Amara SG (1991) Cloning and expression of a cocaine- sensitive rat dopamine transporter. Science 254: 578–579. 69. Shimada S, Kitayama S, Lin CL, Patel A, Nanthakumar E, et al. (1991) Cloning and expression of a cocaine-sensitive dopamine transporter comple- mentary DNA. Science 254: 576–578. 70. Huotari M, Santha M, Lucas LR, Karayiorgou M, Gogos JA, et al. (2002) Effect of dopamine uptake inhibition on brain catecholamine levels and locomotion in catechol-O-methyltransferase-disrupted mice. J Pharmacol Exp Ther 303: 1309–1316. 71. McDonald PW, Hardie SL, Jessen TN, Carvelli L, Matthies DS, et al. (2007) Vigorous motor activity in Caenorhabditis elegans requires efficient clearance of dopamine mediated by synaptic localization of the dopamine transporter DAT-1. J Neurosci 27: 14216–14227. 72. Nass R, Hahn MK, Jessen T, McDonald PW, Carvelli L, et al. (2005) A genetic screen in Caenorhabditis elegans for dopamine neuron insensitivity to 6- hydroxydopamine identifies dopamine transporter mutants impacting trans- porter biosynthesis and trafficking. J Neurochem 94: 774–785. 73. Archibald FS, Tyree C (1987) Manganese poisoning and the attack of trivalent manganese upon catecholamines. Arch Biochem Biophys 256: 638–650. 74. Graham DG (1984) Catecholamine toxicity: a proposal for the molecular pathogenesis of manganese neurotoxicity and Parkinson’s disease. Neurotox- icology 5: 83–95. 75. Sistrunk SC, Ross MK, Filipov NM (2007) Direct effects of manganese compounds on dopamine and its metabolite Dopac: an in vitro study. Environ Toxicol Pharmacol 23: 286–296. 76. Paris I, Dagnino-Subiabre A, Marcelain K, Bennett LB, Caviedes P, et al. (2001) Copper neurotoxicity is dependent on dopamine-mediated copper uptake and one-electron reduction of aminochrome in a rat substantia nigra neuronal cell line. J Neurochem 77: 519–529. 77. Pong K, Doctrow SR, Baudry M (2000) Prevention of 1-methyl-4- phenylpyridinium- and 6-hydroxydopamine-induced nitration of tyrosine hydroxylase and neurotoxicity by EUK-134, a superoxide dismutase and catalase mimetic, in cultured dopaminergic neurons. Brain Res 881: 182–189. 78. Chase DL, Pepper JS, Koelle MR (2004) Mechanism of extrasynaptic dopamine signaling in Caenorhabditis elegans. Nat Neurosci 7: 1096–1103. 79. Lin YT, Hoang H, Hsieh SI, Rangel N, Foster AL, et al. (2006) Manganous ion supplementation accelerates wild type development, enhances stress resistance, and rescues the life span of a short-lived Caenorhabditis elegans mutant. Free Radic Biol Med 40: 1185–1193. 80. Singer TP, Ramsay RR, Ackrell BA (1995) Deficiencies of NADH and succinate dehydrogenases in degenerative diseases and myopathies. Biochim Biophys Acta 1271: 211–219. 81. Bockelmann R, Wolf G, Ransmayr G, Riederer P (1994) NADPH-diaphorase/ nitric oxide synthase containing neurons in normal and Parkinson’s disease putamen. J Neural Transm Park Dis Dement Sect 7: 115–121. 82. Jenner P (1991) Oxidative stress as a cause of Parkinson’s disease. Acta Neurol Scand Suppl 136: 6–15. 83. Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53 Suppl 3: S26–36; discussion S36–28. 84. Cassarino DS, Fall CP, Swerdlow RH, Smith TS, Halvorsen EM, et al. (1997) Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson’s disease. Biochim Biophys Acta 1362: 77–86. 85. Yoo MS, Chun HS, Son JJ, DeGiorgio LA, Kim DJ, et al. (2003) Oxidative stress regulated genes in nigral dopaminergic neuronal cells: correlation with the known pathology in Parkinson’s disease. Brain Res Mol Brain Res 110: 76–84. 86. Wu DC, Teismann P, Tieu K, Vila M, Jackson-Lewis V, et al. (2003) NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydro- pyridine model of Parkinson’s disease. Proc Natl Acad Sci U S A 100: 6145–6150. 87. Lotharius J, Dugan LL, O’Malley KL (1999) Distinct mechanisms underlie neurotoxin-mediated cell death in cultured dopaminergic neurons. J Neurosci 19: 1284–1293. 88. Schapira AH (1995) Oxidative stress in Parkinson’s disease. Neuropathol Appl Neurobiol 21: 3–9. 89. Linert W, Herlinger E, Jameson RF, Kienzl E, Jellinger K, et al. (1996) Dopamine, 6-hydroxydopamine, iron, and dioxygen–their mutual interactions and possible implication in the development of Parkinson’s disease. Biochim Biophys Acta 1316: 160–168. 90. Milne GL, Yin H, Brooks JD, Sanchez S, Jackson Roberts L, 2nd, et al. (2007) Quantification of F2-isoprostanes in biological fluids and tissues as a measure of oxidant stress. Methods Enzymol 433: 113–126. 91. Fam SS, Morrow JD (2003) The isoprostanes: unique products of arachidonic acid oxidation-a review. Curr Med Chem 10: 1723–1740. 92. Taber DF, Morrow JD, Roberts LJ, 2nd (1997) A nomenclature system for the isoprostanes. Prostaglandins 53: 63–67. 93. Oliveira RP, Porter Abate J, Dilks K, Landis J, Ashraf J, et al. (2009) Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf. Aging Cell 8: 524–541. PLoS Genetics | www.plosgenetics.org 16 August 2010 | Volume 6 | Issue 8 | e1001084