The understanding of manganese (Mn) biology, in particular its cellular regulation and role in neurological disease, is an area of expanding interest. Mn is an essential micronutrient that is required for the activity of a diverse set of enzymatic proteins (e.g., arginase and glutamine synthase). Although necessary for life, Mn is toxic in excess. Thus, maintaining appropriate levels of intracellular Mn is critical. Unlike other essential metals, cell-level homeostatic mechanisms of Mn have not been identified. In this review, we discuss common forms of Mn exposure, absorption, and transport via regulated uptake/exchange at the gut and blood-brain barrier and via biliary excretion. We present the current understanding of cellular uptake and efflux as well as subcellular storage and transport of Mn. In addition, we highlight the Mn-dependent and Mn-responsive pathways implicated in the growing evidence of its role in Parkinson's disease and Huntington's disease. We conclude with suggestions for future focuses of Mn health-related research.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Aggarwal A, Vaidya S, Shah S, Singh J, Desai S, Bhatt M. 1.  2006. Reversible Parkinsonism and T1W pallidal hyperintensities in acute liver failure. Mov. Disord. 21:1986–90 [Google Scholar]
  2. Ahmed SS, Santosh W. 2.  2010. Metallomic profiling and linkage map analysis of early Parkinson's disease: a new insight to aluminum marker for the possible diagnosis. PLOS ONE 5:e11252 [Google Scholar]
  3. Akatsu H, Hori A, Yamamoto T, Yoshida M, Mimuro M. 3.  et al. 2012. Transition metal abnormalities in progressive dementias. Biometals 25:337–50 [Google Scholar]
  4. Alves G, Thiebot J, Tracqui A, Delangre T, Guedon C, Lerebours E. 4.  1997. Neurologic disorders due to brain manganese deposition in a jaundiced patient receiving long-term parenteral nutrition. J. Parenter. Enteral Nutr. 21:41–45 [Google Scholar]
  5. Ambrose M, Goldstine JV, Gatti RA. 5.  2007. Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells. Hum. Mol. Genet. 16:2154–64 [Google Scholar]
  6. Andersen ME, Gearhart JM, Clewell HJ 3rd. 6.  1999. Pharmacokinetic data needs to support risk assessments for inhaled and ingested manganese. Neurotoxicology 20:161–71 [Google Scholar]
  7. Anderson JG, Fordahl SC, Cooney PT, Weaver TL, Colyer CL, Erikson KM. 7.  2008. Manganese exposure alters extracellular GABA, GABA receptor and transporter protein and mRNA levels in the developing rat brain. Neurotoxicology 29:1044–53 [Google Scholar]
  8. Andreassen OA, Ferrante RJ, Dedeoglu A, Albers DW, Klivenyi P. 8.  et al. 2001. Mice with a partial deficiency of manganese superoxide dismutase show increased vulnerability to the mitochondrial toxins malonate, 3-nitropropionic acid, and MPTP. Exp. Neurol. 167:189–95 [Google Scholar]
  9. Antoons G, Mubagwa K, Nevelsteen I, Sipido KR. 9.  2002. Mechanisms underlying the frequency dependence of contraction and [Ca2+]i transients in mouse ventricular myocytes. J. Physiol. 543:889–98 [Google Scholar]
  10. Aschner JL, Aschner M. 10.  2005. Nutritional aspects of manganese homeostasis. Mol. Aspects Med. 26:353–62 [Google Scholar]
  11. Aschner M, Aschner JL. 11.  1990. Manganese transport across the blood-brain barrier: relationship to iron homeostasis. Brain Res. Bull. 24:857–60 [Google Scholar]
  12. Aschner M, Gannon M. 12.  1994. Manganese (Mn) transport across the rat blood-brain barrier: saturable and transferrin-dependent transport mechanisms. Brain Res. Bull. 33:345–49 [Google Scholar]
  13. Aschner M, Guilarte TR, Schneider JS, Zheng W. 13.  2007. Manganese: recent advances in understanding its transport and neurotoxicity. Toxicol. Appl. Pharmacol. 221:131–47 [Google Scholar]
  14. 14. ATSDR (Agency Toxic Subst. Dis. Regist.) 2008. Toxicological profile for manganese. Atlanta, GA: ATSDR http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=102&tid=23 [Google Scholar]
  15. Au C, Benedetto A, Anderson J, Labrousse A, Erikson K. 15.  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 [Google Scholar]
  16. Ayton S, Lei P, Duce JA, Wong BXW, Sedjahtera A. 16.  et al. 2013. Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Ann. Neurol. 73:554–59 [Google Scholar]
  17. Bagga P, Patel AB. 17.  2012. Regional cerebral metabolism in mouse under chronic manganese exposure: implications for manganism. Neurochem. Int. 60:177–85 [Google Scholar]
  18. Banin S, Moyal L, Shieh S, Taya Y, Anderson CW. 18.  et al. 1998. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281:1674–77 [Google Scholar]
  19. Bassani JW, Bassani RA, Bers DM. 19.  1994. Relaxation in rabbit and rat cardiac cells: species-dependent differences in cellular mechanisms. J. Physiol. 476:279–93 [Google Scholar]
  20. Behrens PF, Franz P, Woodman B, Lindenberg KS, Landwehrmeyer GB. 20.  2002. Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation. Brain 125:1908–22 [Google Scholar]
  21. Bell JG, Keen CL, Lonnerdal B. 21.  1989. Higher retention of manganese in suckling than in adult rats is not due to maturational differences in manganese uptake by rat small intestine. J. Toxicol. Environ. Health 26:387–98 [Google Scholar]
  22. Berkowitz DE, White R, Li D, Minhas KM, Cernetich A. 22.  et al. 2003. Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation 108:2000–6 [Google Scholar]
  23. Bhang SY, Cho SC, Kim JW, Hong YC, Shin MS. 23.  et al. 2013. Relationship between blood manganese levels and children's attention, cognition, behavior, and academic performance—a nationwide cross-sectional study. Environ. Res. 126:9–16 [Google Scholar]
  24. Boaru SG, Merle U, Uerlings R, Zimmermann A, Weiskirchen S. 24.  et al. 2014. Simultaneous monitoring of cerebral metal accumulation in an experimental model of Wilson's disease by laser ablation inductively coupled plasma mass spectrometry. BMC Neurosci. 15:98 [Google Scholar]
  25. Bornhorst J, Wehe CA, Huwel S, Karst U, Galla HJ, Schwerdtle T. 25.  2012. Impact of manganese on and transfer across blood-brain and blood-cerebrospinal fluid barrier in vitro. J. Biol. Chem. 287:17140–51 [Google Scholar]
  26. Bosomworth HJ, Adlard PA, Ford D, Valentine RA. 26.  2013. Altered expression of ZnT10 in Alzheimer's disease brain. PLOS ONE 8:e65475 [Google Scholar]
  27. Bowman AB, Aschner M. 27.  2014. Considerations on manganese (Mn) treatments for in vitro studies. Neurotoxicology 41:141–42 [Google Scholar]
  28. Bowman AB, Kwakye GF, Herrero Hernandez E, Aschner M. 28.  2011. Role of manganese in neurodegenerative diseases. J. Trace Elements Med. Biol. 25:191–203 [Google Scholar]
  29. Braissant O, Gotoh T, Loup M, Mori M, Bachmann C. 29.  1999. L-arginine uptake, the citrulline-NO cycle and arginase II in the rat brain: an in situ hybridization study. Mol. Brain Res. 70:231–41 [Google Scholar]
  30. Britton AA, Cotzias GC. 30.  1966. Dependence of manganese turnover on intake. Am. J. Physiol. 211:203–6 [Google Scholar]
  31. Brock AA, Chapman SA, Ulaman EA, Wu G. 31.  1993. Dietary manganese deficiency decreases rat hepatic arginase activity. J. Nutr. 124:340–44 [Google Scholar]
  32. Brouillet E. 32.  2014. The 3-NP model of striatal neurodegeneration. Curr. Protoc. Neurosci. 67:9.48.1–14 [Google Scholar]
  33. Buettner GR, Ng CF, Wang M, Rodgers VGJ, Schafer FQ. 33.  2006. A new paradigm: manganese superoxide dismutase influences the production of H2O2 in cells and thereby their biological state. Free Radic. Biol. Med. 41:1338–50 [Google Scholar]
  34. Burdo JR, Menzies SL, Simpson IA, Garrick LM, Garrick MD. 34.  et al. 2001. Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J. Neurosci. Res. 66:1198–207 [Google Scholar]
  35. Burkhard PR, Delavelle J, Pasquier RD, Spahr L. 35.  2003. Chronic Parkinsonism associated with cirrhosis: a distinct subset of acquired hepatocerebral degeneration. Arch. Neurol. 60:521–28 [Google Scholar]
  36. Butterworth J. 36.  1986. Changes in nine enzyme markers for neurons, glia, and endothelial cells in agonal state and Huntington's disease caudate nucleus. J. Neurochem. 47:583–87 [Google Scholar]
  37. Cai T, Che H, Yao T, Chen Y, Huang C. 37.  et al. 2011. Manganese induces tau hyperphosphorylation through the activation of ERK MAPK pathway in PC12 cells. Toxicol. Sci. 119:169–77 [Google Scholar]
  38. Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K. 38.  et al. 1998. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281:1677–79 [Google Scholar]
  39. Carmona A, Roudeau S, Perrin L, Veronesi G, Ortega R. 39.  2014. Environmental manganese compounds accumulate as Mn(II) within the Golgi apparatus of dopamine cells: relationship between speciation, subcellular distribution, and cytotoxicity. Metallomics 6:822–32 [Google Scholar]
  40. Carter CJ. 40.  1982. Glutamine synthetase activity in Huntington's disease. Life Sci. 31:1151–59 [Google Scholar]
  41. Chan DW. 41.  2000. Purification and characterization of ATM from human placenta. A manganese-dependent, Wortmannin-sensitive serine/threonine protein kinase. J. Biol. Chem. 275:7803–10 [Google Scholar]
  42. Chen J, Marks E, Lai B, Zhang Z, Duce JA. 42.  et al. 2013. Iron accumulates in Huntington's disease neurons: protection by deferoxamine. PLOS ONE 8:e77023 [Google Scholar]
  43. Chen L, Ding G, Gao Y, Wang P, Shi R. 43.  et al. 2014. Manganese concentrations in maternal-infant blood and birth weight. Environ. Sci. Pollut. Res. Int. 21:6170–75 [Google Scholar]
  44. Chiang MC, Chen HM, Lai HL, Chen HW, Chou SY. 44.  et al. 2009. The A2A adenosine receptor rescues the urea cycle deficiency of Huntington's disease by enhancing the activity of the ubiquitin-proteasome system. Hum. Mol. Genet. 18:2929–42 [Google Scholar]
  45. Chiang MC, Chen HM, Lee YH, Chang HH, Wu YC. 45.  et al. 2007. Dysregulation of C/EBPα by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease. Hum. Mol. Genet. 16:483–98 [Google Scholar]
  46. Chun HS, Lee HH, Son JH. 46.  2001. Manganese induces endoplasmic reticulum (ER) stress and activates multiple caspases in nigral dopaminergic neuronal cells, SN4741. Neurosci. Lett. 316:5–8 [Google Scholar]
  47. Cohn JR, Emmett EA. 47.  1978. The excretion of trace metals in human sweat. Ann. Clin. Lab. Sci. 8:270–75 [Google Scholar]
  48. Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP. 48.  2006. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J. Neuroinflammation 3:27 [Google Scholar]
  49. Cordova FM, Aguiar AS Jr, Peres TV, Lopes MW, Goncalves FM. 49.  et al. 2013. Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox. Arch. Toxicol. 87:1231–44 [Google Scholar]
  50. Cordova FM, Aguiar AS Jr, Peres TV, Lopes MW, Goncalves FM. 50.  et al. 2012. In vivo manganese exposure modulates Erk, Akt and Darpp-32 in the striatum of developing rats, and impairs their motor function. PLOS ONE 7:e33057 [Google Scholar]
  51. Criswell SR, Perlmutter JS, Huang JL, Golchin N, Flores HP. 51.  et al. 2012. Basal ganglia intensity indices and diffusion weighted imaging in manganese-exposed welders. Occup. Environ. Med. 69:437–43 [Google Scholar]
  52. Criswell SR, Perlmutter JS, Videen TO, Moerlein SM, Flores HP. 52.  et al. 2011. Reduced uptake of [18F]FDOPA PET in asymptomatic welders with occupational manganese exposure. Neurology 76:1296–301 [Google Scholar]
  53. Crittenden PL, Filipov NM. 53.  2008. Manganese-induced potentiation of in vitro proinflammatory cytokine production by activated microglial cells is associated with persistent activation of p38 MAPK. Toxicol. In Vitro 22:18–27 [Google Scholar]
  54. Crittenden PL, Filipov NM. 54.  2011. Manganese modulation of MAPK pathways: effects on upstream mitogen activated protein kinase kinases and mitogen activated kinase phosphatase-1 in microglial cells. J. Appl. Toxicol. 31:1–10 [Google Scholar]
  55. Crossgrove J, Zheng W. 55.  2004. Manganese toxicity upon overexposure. NMR Biomed. 17:544–53 [Google Scholar]
  56. Crossgrove JS, Allen DD, Bukaveckas BL, Rhineheimer SS, Yokel RA. 56.  2003. Manganese distribution across the blood-brain barrier I. Evidence for carrier-mediated influx of manganese citrate as well as manganese and manganese transferrin. Neurotoxicology 24:3–13 [Google Scholar]
  57. Crossgrove JS, Yokel RA. 57.  2004. Manganese distribution across the blood-brain barrier. III. The divalent metal transporter-1 is not the major mechanism mediating brain manganese uptake. Neurotoxicology 25:451–60 [Google Scholar]
  58. Crossgrove JS, Yokel RA. 58.  2005. Manganese distribution across the blood-brain barrier. IV. Evidence for brain influx through store-operated calcium channels. Neurotoxicology 26:297–307 [Google Scholar]
  59. Czlonkowska A, Kohutnicka M, Kurkowska-Jastrzebska I, Czlonkowski A. 59.  1996. Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson's disease mice model. Neurodegeneration 5:137–43 [Google Scholar]
  60. D'Antonio EL, Hai Y, Christianson DW. 60.  2012. Structure and function of non-native metal clusters in human arginase I. Biochemistry 51:8399–409 [Google Scholar]
  61. Das A Jr, Hammad TA. 61.  2000. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage 8:343–50 [Google Scholar]
  62. Davidsson L, Cederblad A, Lonnerdal B, Sandstrom B. 62.  1991. The effect of individual dietary components on manganese absorption in humans. Am. J. Clin. Nutr. 54:1065–70 [Google Scholar]
  63. Davidsson L, Cederblad A, Lonnerdal B, Sandstrom B. 63.  1989. Manganese absorption from human milk, cow's milk, and infant formulas in humans. Am. J. Dis. Child. 143:823–27 [Google Scholar]
  64. Davidsson L, Loennerdal B, Sandstroem B, Kunz C, Keen CL. 64.  1989. Identification of transferrin as the major plasma carrier protein for manganese introduced orally or intravenously or after in vitro addition in the rat. J. Nutr. 119:1461–64 [Google Scholar]
  65. Davidsson LA, Lonnerdal B. 65.  1989. Fe-saturation and proteolysis of human lactoferrin: effect on brush-border receptor-mediated uptake of Fe and Mn. Am. J. Physiol. 257:G930–34 [Google Scholar]
  66. Davis CD, Greger JL. 66.  1992. Longitudinal changes of manganese-dependent superoxide dismutase and other indexes of manganese and iron status in women. Am. J. Clin. Nutr. 55:747–52 [Google Scholar]
  67. Davis CD, Zech L, Greger JL. 67.  1993. Manganese metabolism in rats: an improved methodology for assessing gut endogenous losses. Proc. Soc. Exp. Biol. Med. 202:103–8 [Google Scholar]
  68. Deckel AW, Tang V, Nuttal D, Gary KA, Elder R. 68.  2002. Altered neuronal nitric oxide synthase expression contributes to disease progression in Huntington's disease transgenic mice. Brain Res. 939:76–86 [Google Scholar]
  69. Deckel AW, Volmer P, Weiner R, Gary KA, Covault J. 69.  et al. 2000. Dietary arginine alters time of symptom onset in Huntington's disease transgenic mice. Brain Res. 875:187–95 [Google Scholar]
  70. Delnooz CC, Wevers RA, Quadri M, Clayton PT, Mills PB. 70.  et al. 2013. Phenotypic variability in a dystonia family with mutations in the manganese transporter gene. Mov. Disord. 28:685–86 [Google Scholar]
  71. Deng K, He H, Qiu J, Lorber B, Bryson JB, Filbin MT. 71.  2009. Increased synthesis of spermidine as a result of upregulation of arginase I promotes axonal regeneration in culture and in vivo. J. Neurosci. 29:9545–52 [Google Scholar]
  72. Dickinson TK, Devenyi AG, Connor JR. 72.  1996. Distribution of injected ion 59 and manganese 54 in hypotransferrinemic mice. J. Lab. Clin. Med. 128:270–78 [Google Scholar]
  73. Dode L, Andersen JP, Raeymaekers L, Missiaen L, Vilsen B, Wuytack F. 73.  2005. Functional comparison between secretory pathway Ca2+/Mn2+-ATPase (SPCA) 1 and sarcoplasmic reticulum Ca2+-ATPase (SERCA) 1 isoforms by steady-state and transient kinetic analyses. J. Biol. Chem. 280:39124–34 [Google Scholar]
  74. Dode L, Andersen JP, Vanoevelen J, Raeymaekers L, Missiaen L. 74.  et al. 2006. Dissection of the functional differences between human secretory pathway Ca2+/Mn2+-ATPase (SPCA) 1 and 2 isoenzymes by steady-state and transient kinetic analyses. J. Biol. Chem. 281:3182–89 [Google Scholar]
  75. Doker S, Mounicou S, Dogan M, Lobinski R. 75.  2010. Probing the metal-homeostatis effects of the administration of chromium(VI) to mice by ICP MS and size-exclusion chromatography-ICP MS. Metallomics 2:549–55 [Google Scholar]
  76. Dorman DC, Struve MF, Clewell HJ 3rd, Andersen ME. 76.  2006. Application of pharmacokinetic data to the risk assessment of inhaled manganese. Neurotoxicology 27:752–64 [Google Scholar]
  77. Dorman DC, Struve MF, James RA, McManus BE, Marshall MW, Wong BA. 77.  2001. Influence of dietary manganese on the pharmacokinetics of inhaled manganese sulfate in male CD rats. Toxicol. Sci. 60:242–51 [Google Scholar]
  78. dos Santos AP, Milatovic D, Au C, Yin Z, Batoreu MC, Aschner M. 78.  2010. Rat brain endothelial cells are a target of manganese toxicity. Brain Res. 1326:152–61 [Google Scholar]
  79. Dumont M, Wille E, Stack C, Calingasan NY, Beal MF, Lin MT. 79.  2009. Reduction of oxidative stress, amyloid deposition, and memory deficit by manganese superoxide dismutase overexpression in a transgenic mouse model of Alzheimer's disease. FASEB J. 23:2459–66 [Google Scholar]
  80. Dydak U, Jiang YM, Long LL, Zhu H, Chen J. 80.  et al. 2011. In vivo measurement of brain GABA concentrations by magnetic resonance spectroscopy in smelters occupationally exposed to manganese. Environ. Health Perspect. 119:219–24 [Google Scholar]
  81. Elder A, Gelein R, Silva V, Feikert T, Opanashuk L. 81.  et al. 2006. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ. Health Perspect. 114:1172–78 [Google Scholar]
  82. Ensunsa JL, Symons JD, Lanoue L, Schrader HR, Keen CL. 82.  2004. Reducing arginase activity via dietary manganese deficiency enhances endothelium-dependent vasorelaxation of rat aorta. Exp. Biol. Med. 229:1143–53 [Google Scholar]
  83. Ergen K, Ince H, Duzova H, Karakoc Y, Emre MH. 83.  2013. Acute effects of moderate and strenuous running on trace element distribution in the brain, liver, and spleen of trained rats. Balkan Med. J. 30:105–10 [Google Scholar]
  84. Erikson K, Aschner M. 84.  2002. Manganese causes differential regulation of glutamate transporter (GLAST) taurine transporter and metallothionein in cultured rat astrocytes. Neurotoxicology 23:595–602 [Google Scholar]
  85. Erikson KM, Suber RL, Aschner M. 85.  2002. Glutamate/aspartate transporter (GLAST), taurine transporter and metallothionein mRNA levels are differentially altered in astrocytes exposed to manganese chloride, manganese phosphate or manganese sulfate. Neurotoxicology 23:281–88 [Google Scholar]
  86. Esch F, Lin K, Hills A, Baraban JM, Chatterjee S. 86.  et al. 1998. Purification of a multipotent antideath activity from bovine liver and its identification as arginase: nitric oxide-independent inhibition of neuronal apoptosis. J. Neurosci. 18:4083–95 [Google Scholar]
  87. Estevez AG, Sahawneh MA, Lange PS, Bae N, Egea M, Ratan RR. 87.  2006. Arginase 1 regulation of nitric oxide production is key to survival of trophic factor-deprived motor neurons. J. Neurosci. 26:8512–16 [Google Scholar]
  88. Eum JH, Cheong HK, Ha EH, Ha M, Kim Y. 88.  et al. 2014. Maternal blood manganese level and birth weight: a MOCEH birth cohort study. Environ. Health 13:31 [Google Scholar]
  89. Fallon EM, Le HD, Puder M. 89.  2010. Prevention of parenteral nutrition-associated liver disease: role of omega-3 fish oil. Curr. Opin. Organ Transplant. 15:334–40 [Google Scholar]
  90. Ferlazzo ML, Sonzogni L, Granzotto A, Bodgi L, Lartin O. 90.  et al. 2014. Mutations of the Huntington's disease protein impact on the ATM-dependent signaling and repair pathways of the radiation-induced DNA double-strand breaks: corrective effect of statins and bisphosphonates. Mol. Neurobiol. 49:1200–11 [Google Scholar]
  91. Filipov NM, Seegal RF, Lawrence DA. 91.  2005. Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism. Toxicol. Sci. 84:139–48 [Google Scholar]
  92. Finkelstein Y, Zhang N, Fitsanakis VA, Avison MJ, Gore JC, Aschner M. 92.  2008. Differential deposition of manganese in the rat brain following subchronic exposure to manganese: a T1-weighted magnetic resonance imaging study. Israel Med. Assoc. J. 10:793–98 [Google Scholar]
  93. Finley JW, Johnson PE, Johnson LK. 93.  1994. Sex affects manganese absorption and retention by humans from a diet adequate in manganese. Am. J. Clin. Nutr. 60:949–55 [Google Scholar]
  94. Fitsanakis VA, Piccola G, Aschner JL, Aschner M. 94.  2006. Characteristics of manganese (Mn) transport in rat brain endothelial (RBE4) cells, an in vitro model of the blood-brain barrier. Neurotoxicology 27:60–70 [Google Scholar]
  95. Fitsanakis VA, Piccola G, Aschner JL, Aschner M. 95.  2005. Manganese transport by rat brain endothelial (RBE4) cell-based Transwell model in the presence of astrocyte conditioned media. J. Neurosci. Res. 81:235–43 [Google Scholar]
  96. Fitsanakis VA, Zhang N, Anderson JG, Erikson KM, Avison MJ. 96.  et al. 2008. Measuring brain manganese and iron accumulation in rats following 14 weeks of low-dose manganese treatment using atomic absorption spectroscopy and magnetic resonance imaging. Toxicol. Sci. 103:116–24 [Google Scholar]
  97. Fitsanakis VA, Zhang N, Avison MJ, Erikson KM, Gore JC, Aschner M. 97.  2011. Changes in dietary iron exacerbate regional brain manganese accumulation as determined by magnetic resonance imaging. Toxicol. Sci. 120:146–53 [Google Scholar]
  98. Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC. 98.  1998. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. PNAS 95:1148–53 [Google Scholar]
  99. Foradori AC, Bertinchamps A, Gulibon JM, Cotzias GC. 99.  1967. The discrimination between magnesium and manganese by serum proteins. J. Gen. Physiol. 50:2255–66 [Google Scholar]
  100. Forbes JR, Gros P. 100.  2003. Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood 102:1884–92 [Google Scholar]
  101. Fordahl SC, Anderson JG, Cooney PT, Weaver TL, Colyer CL, Erikson KM. 101.  2010. Manganese exposure inhibits the clearance of extracellular GABA and influences taurine homeostasis in the striatum of developing rats. Neurotoxicology 31:639–46 [Google Scholar]
  102. Frankel D. 102.  1993. Supplementation of trace elements in parenteral nutrition: rationale and recommendations. Nutr. Res. 13:583–96 [Google Scholar]
  103. Friedman BJ, Freeland-Graves JH, Bales CW, Behmardi F, Shorey-Kutschke RL. 103.  et al. 1987. Manganese balance and clinical observations in young men fed a manganese-deficient diet. J. Nutr. 117:133–43 [Google Scholar]
  104. Fujishiro H, Ohashi T, Takuma M, Himeno S. 104.  2013. Suppression of ZIP8 expression is a common feature of cadmium-resistant and manganese-resistant RBL-2H3 cells. Metallomics 5:437–44 [Google Scholar]
  105. Fujishiro H, Yoshida M, Nakano Y, Himeno S. 105.  2014. Interleukin-6 enhances manganese accumulation in SH-SY5Y cells: implications of the up-regulation of ZIP14 and the down-regulation of ZnT10. Metallomics 6:944–49 [Google Scholar]
  106. Garcia-Aranda JA, Wapnir RA, Lifshitz F. 106.  1983. In vivo intestinal absorption of manganese in the rat. J. Nutr. 113:2601–7 [Google Scholar]
  107. Garcia SJ, Gellein K, Syversen T, Aschner M. 107.  2007. Iron deficient and manganese supplemented diets alter metals and transporters in the developing rat brain. Toxicol. Sci. 95:205–14 [Google Scholar]
  108. Garrick MD, Dolan KG, Hobinski C, Ghio AJ, Higgins D. 108.  et al. 2003. DMT1: a mammalian transporter for multiple metals. Biometals 16:41–54 [Google Scholar]
  109. Gavin CE, Gunter KK, Gunter TE. 109.  1990. Manganese and calcium efflux kinetics in brain mitochondria. Biochem. J. 266:329–34 [Google Scholar]
  110. Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S. 110.  et al. 2009. Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat. Genet. 41:308–15 [Google Scholar]
  111. Gorovitz RA, Avisar N, Shaked I, Vardimon L. 111.  1997. Glutamine synthetase protects against neuronal degeneration in injured retinal tissue. PNAS 94:7024–29 [Google Scholar]
  112. Goytain A, Hines RM, Quamme GA. 112.  2008. Huntingtin-interacting proteins, HIP14 and HIP14L, mediate dual functions, palmitoyl acyltransferase and Mg2+ transport. J. Biol. Chem. 283:33365–74 [Google Scholar]
  113. Graham MF, Tavill AS, Halpin TC, Louis LN. 113.  1984. Inhibition of bile flow in the isolated perfused rat liver by a synthetic parenteral amino acid mixture: associated net amino acid fluxes. Hepatology 4:69–73 [Google Scholar]
  114. Greger JL. 114.  1998. Dietary standards for manganese: overlap between nutritional and toxicological studies. J. Nutr. 128:368–71S [Google Scholar]
  115. Grimm C, Kraft R, Sauerbruch S, Schultz G, Harteneck C. 115.  2003. Molecular and functional characterization of the melastatin-related cation channel TRPM3. J. Biol. Chem. 278:21493–501 [Google Scholar]
  116. Gruenheid S, Canonne-Hergaux F, Gauthier S, Hackam DJ, Grinstein S, Gros P. 116.  1999. The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. J. Exp. Med. 189:831–41 [Google Scholar]
  117. Guilarte TR. 117.  2010. APLP1, Alzheimer's-like pathology and neurodegeneration in the frontal cortex of manganese-exposed non-human primates. Neurotoxicology 31:572–74 [Google Scholar]
  118. Guilarte TR, Burton NC, Verina T, Prabhu VV, Becker KG. 118.  et al. 2008. Increased APLP1 expression and neurodegeneration in the frontal cortex of manganese-exposed non-human primates. J. Neurochem. 105:1948–59 [Google Scholar]
  119. Guilarte TR, Chen MK, McGlothan JL, Verina T, Wong DF. 119.  et al. 2006. Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates. Exp. Neurol. 202:381–90 [Google Scholar]
  120. Guilbert A, Gautier M, Dhennin-Duthille I, Haren N, Sevestre H, Ouadid-Ahidouch H. 120.  2009. Evidence that TRPM7 is required for breast cancer cell proliferation. Am. J. Physiol. Cell Physiol. 297:C493–502 [Google Scholar]
  121. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF. 121.  et al. 1997. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 338:482–88 [Google Scholar]
  122. Gunter TE, Gavin CE, Aschner M, Gunter KK. 122.  2006. Speciation of manganese in cells and mitochondria: a search for the proximal cause of manganese neurotoxicity. Neurotoxicology 27:765–76 [Google Scholar]
  123. Gunter TE, Gerstner B, Gunter KK, Malecki J, Gelein R. 123.  et al. 2013. Manganese transport via the transferrin mechanism. Neurotoxicology 34:118–27 [Google Scholar]
  124. Gunteski Hamblin AM, Clarke DM, Shull GE. 124.  1992. Molecular cloning and tissue distribution of alternatively spliced mRNAs encoding possible mammalian homologues of the yeast secretory pathway calcium pump. Biochemistry 31:7600–8 [Google Scholar]
  125. Guo ZK, Kozlov S, Lavin MF, Person MD, Paull TT. 125.  2010. ATM activation by oxidative stress. Science 330:517–21 [Google Scholar]
  126. Hansen SL, Trakooljul N, Liu HC, Moeser AJ, Spears JW. 126.  2009. Iron transporters are differentially regulated by dietary iron, and modifications are associated with changes in manganese metabolism in young pigs. J. Nutr. 139:1474–79 [Google Scholar]
  127. Hare DJ, George JL, Grimm R, Wilkins S, Adlard PA. 127.  et al. 2010. Three-dimensional elemental bio-imaging of Fe, Zn, Cu, Mn and P in a 6-hydroxydopamine lesioned mouse brain. Metallomics 2:745–53 [Google Scholar]
  128. Harris WR, Chen Y. 128.  1994. Electron paramagnetic resonance and difference ultraviolet studies of Mn2+ binding to serum transferrin. J. Inorg. Biochem. 54:1–19 [Google Scholar]
  129. Hassel B, Bachelard H, Jones P, Fonnum F, Sonnewald U. 129.  1997. Trafficking of amino acids between neurons and glia in vivo. Effects of inhibition of glial metabolism by fluoroacetate. J. Cereb. Blood Flow Metab. 17:1230–38 [Google Scholar]
  130. He L, Girijashanker K, Dalton TP, Reed J, Li H. 130.  et al. 2006. ZIP8, member of the solute-carrier-39 (SLC39) metal-transporter family: characterization of transporter properties. Mol. Pharmacol. 70:171–80 [Google Scholar]
  131. Herrero Hernandez E, Discalzi G, Valentini C, Venturi F, Chio A. 131.  et al. 2006. Follow-up of patients affected by manganese-induced Parkinsonism after treatment with CaNa2EDTA. Neurotoxicology 27:333–39 [Google Scholar]
  132. Hertz LY, Yu A, Svenneby G, Kvamme E, Fosmark H, Schousboe A. 132.  1980. Absence of preferential glutamine uptake into neurons—an indication of a net transfer of TCA constituents from nerve endings to astrocytes?. Neurosci. Lett. 16:103–9 [Google Scholar]
  133. Higashi Y, Asanuma M, Miyazaki I, Hattori N, Mizuno Y, Ogawa N. 133.  2004. Parkin attenuates manganese-induced dopaminergic cell death. J. Neurochem. 89:1490–97 [Google Scholar]
  134. Hirata Y, Furuta K, Miyazaki S, Suzuki M, Kiuchi K. 134.  2004. Anti-apoptotic and pro-apoptotic effect of NEPP11 on manganese-induced apoptosis and JNK pathway activation in PC12 cells. Brain Res.1021241–47 [Google Scholar]
  135. Hopfner K, Karcher A, Craig L, Woo TT, Carney JP, Tainer JA. 135.  2001. Structural biochemistry and interaction architecture of the DNA double-strand break repair Mre11 nuclease and Rad50-ATPase. Cell 105:473–85 [Google Scholar]
  136. Hozumi I, Hasegawa T, Honda A, Ozawa K, Hayashi Y. 136.  et al. 2011. Patterns of levels of biological metals in CSF differ among neurodegenerative diseases. J. Neurol. Sci. 303:95–99 [Google Scholar]
  137. Huang E, Ong WY, Connor JR. 137.  2004. Distribution of divalent metal transporter-1 in the monkey basal ganglia. Neuroscience 128:487–96 [Google Scholar]
  138. Huang K, Sanders SS, Kang R, Carroll JB, Sutton L. 138.  et al. 2011. Wild-type HTT modulates the enzymatic activity of the neuronal palmitoyl transferase HIP14. Hum. Mol. Genet. 20:3356–65 [Google Scholar]
  139. Huang K, Yanai A, Kang R, Arstikaitis P, Singaraja RR. 139.  et al. 2004. Huntingtin-interacting protein HIP14 is a palmitoyl transferase involved in palmitoylation and trafficking of multiple neuronal proteins. Neuron 44:977–86 [Google Scholar]
  140. Iinuma Y, Kubota M, Uchiyama M, Yagi M, Kanada S. 140.  et al. 2003. Whole-blood manganese levels and brain manganese accumulation in children receiving long-term home parenteral nutrition. Pediatr. Surg. Int. 19:268–72 [Google Scholar]
  141. Jursa T, Smith DR. 141.  2009. Ceruloplasmin alters the tissue disposition and neurotoxicity of manganese, but not its loading onto transferrin. Toxicol. Sci. 107:182–93 [Google Scholar]
  142. Kalia K, Jiang W, Zheng W. 142.  2008. Manganese accumulates primarily in nuclei of cultured brain cells. Neurotoxicology 29:466–70 [Google Scholar]
  143. Kannurpatti SS, Joshi PG, Joshi NB. 143.  2000. Calcium sequestering ability of mitochondria modulates influx of calcium through glutamate receptor channel. Neurochem. Res. 25:1527–36 [Google Scholar]
  144. Kanyo ZF, Scolnick LR, Ash DE, Christianson DW. 144.  1996. Structure of a unique binuclear manganese cluster in arginase. Nature 383:554–57 [Google Scholar]
  145. Keefer RC, Barak AJ, Boyett JD. 145.  1970. Binding of manganese and transferrin in rat serum. Biochim. Biophys. Acta 221:390–93 [Google Scholar]
  146. Keen CL, Bell JG, Lonnerdal B. 146.  1986. The effect of age on manganese uptake and retention from milk and infant formulas in rats. J. Nutr. 116:395–402 [Google Scholar]
  147. Keen CL, Ensunsa JL, Watson MH, Baly DL, Donovan SM. 147.  et al. 1999. Nutritional aspects of manganese from experimental studies. Neurotoxicology 20:213–23 [Google Scholar]
  148. Keller JN, Kindy MS, Holtsberg FW, St Clair DK, Yen HC. 148.  et al. 1998. Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J. Neurosci. 18:687–97 [Google Scholar]
  149. Kobayashi K, Kuroda J, Shibata N, Hasegawa T, Seko Y. 149.  et al. 2007. Induction of metallothionein by manganese is completely dependent on interleukin-6 production. J. Pharmacol. Exp. Ther. 320:721–27 [Google Scholar]
  150. Kong SM, Chan BK, Park JS, Hill KJ, Aitken JB. 150.  et al. 2014. Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-Synuclein externalization via exosomes. Hum. Mol. Genet. 23:2816–33 [Google Scholar]
  151. Kozlov S. 151.  2003. ATP activates ataxia-telangiectasia mutated (ATM) in vitro. Importance of autophosphorylation. J. Biol. Chem. 278:9309–17 [Google Scholar]
  152. Krishna S, Dodd CA, Hekmatyar SK, Filipov NM. 152.  2014. Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water. Arch. Toxicol. 88:47–64 [Google Scholar]
  153. Kulijewicz-Nawrot M, Sykova E, Chvatal A, Verkhratsky A, Rodriguez JJ. 153.  2013. Astrocytes and glutamate homoeostasis in Alzheimer's disease: a decrease in glutamine synthetase, but not in glutamate transporter-1, in the prefrontal cortex. ASN Neuro 5:273–82 [Google Scholar]
  154. Kumar KK, Lowe EW Jr, Aboud AA, Neely MD, Redha R. 154.  et al. 2014. Cellular manganese content is developmentally regulated in human dopaminergic neurons. Sci. Rep. 4:6801 [Google Scholar]
  155. Kuo HS, Tsai MJ, Huang MC, Chiu CW, Tsai CY. 155.  et al. 2011. Acid fibroblast growth factor and peripheral nerve grafts regulate Th2 cytokine expression, macrophage activation, polyamine synthesis, and neurotrophin expression in transected rat spinal cords. J. Neurosci. 31:4137–47 [Google Scholar]
  156. Lawson LJ, Perry VH, Dri P, Gordon S. 156.  1990. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–70 [Google Scholar]
  157. Leblondel G, Allain P. 157.  1999. Manganese transport by Caco-2 cells. Biol. Trace Element Res. 67:13–28 [Google Scholar]
  158. Lebovitz RM, Zhang H, Vogel H, Cartwright JJ, Dionne L. 158.  et al. 1996. Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. PNAS 93:9782–87 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error