Metallothioneins and the central nervous system: From a deregulation in neurodegenerative diseases to the development of new therapeutic approaches

Journal of Alzheimer's Disease

Volumn 41, Issue 1, 2014, Pages 29-42

  Bolognin, Silvia ^a   Cozzi, Bruno ^b   Zambenedetti, Pamela ^c   Zatta, Paolo ^b  

^a UNIVERSITY OF VERONA   (Italy)

^b UNIVERSITY OF PADOVA   (Italy)

^c GENERAL HOSPITAL   (Italy)

Author keywords

Brain development; metal ions; metallothioneins; neurodegenerative diseases

Indexed keywords

FREE RADICAL; METAL; METALLOTHIONEIN; METALLOTHIONEIN I; METALLOTHIONEIN II; METALLOTHIONEIN III;

ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; BINSWANGER ENCEPHALOPATHY; BRAIN DEVELOPMENT; CENTRAL NERVOUS SYSTEM; DEGENERATIVE DISEASE; HUMAN; MULTIINFARCT DEMENTIA; NERVE DEGENERATION; NERVOUS SYSTEM INJURY; NEUROPROTECTION; NONHUMAN; OXIDATIVE STRESS; PARKINSON DISEASE; PRION DISEASE; PRIORITY JOURNAL; PROTEIN FAMILY; REVIEW; ANIMAL; BRAIN; DRUG EFFECTS; GROWTH, DEVELOPMENT AND AGING; METABOLISM; NEURODEGENERATIVE DISEASES; PATHOPHYSIOLOGY;

ANIMALS; BRAIN; HUMANS; METALLOTHIONEIN; NEURODEGENERATIVE DISEASES;

EID: 84902282100     PISSN: 13872877     EISSN: 18758908     Source Type: Journal    
DOI: 10.3233/JAD-130290     Document Type: Review

References (145)

1. Palacios O, Atrian S, Capdevila M (2011) Zn-and Cu-thioneins: A functional classification for metallothioneins? J Biol Inorg Chem 16, 991-1009.
2. Vasak M, Meloni G (2011) Chemistry and biology of mammalian metallothioneins. J Biol Inorg Chem 16, 1067-1078.
3. Faller P (2010) Neuronal growth-inhibitory factor (metallothionein-3): Reactivity and structure of metal-thiolate clusters. FEBS J 277, 2921-2930.
4. Ding ZC, Ni FY, Huang ZX (2010) Neuronal growth-inhibitory factor (metallothionein-3): Structure-function relationships. FEBS J 277, 2912-2920.
5. Hidalgo J, Aschner M, Zatta P, Vasak M (2001) Roles of the metallothionein family of proteins in the central nervous system. Brain Res Bull 55, 133-145.
6. Kruczek C, Gorg B, Keitel V, Bidmon HJ, Schliess F, Haussinger D (2011) Ammonia increases nitric oxide, free Zn (2+), and metallothionein mRNA expression in cultured rat astrocytes. Biol Chem 392, 1155-1165.
7. Lynes MA, Fontenot AP, Lawrence DA, Rosenspire AJ, Pollard KM (2006) Gene expression influences on metal immunomodulation. Toxicol Appl Pharmacol 210, 9-16.
8. Gasull T, Giralt M, Hernandez J, Martinez P, Bremner I, Hidalgo J (1994) Regulation of metallothionein concentrations in rat brain: Effect of glucocorticoids, zinc, copper, and endotoxin. Am J Physiol 266, E760-E767.
9. Miles AT, Hawksworth GM, Beattie JH, Rodilla V (2000) Induction, regulation, degradation, and biological significance of mammalian metallothioneins. Crit Rev Biochem Mol Biol 35, 35-70.
10. Bolognin S, Messori L, Zatta P (2009) Metal ion physiopathology in neurodegenerative disorders. Neuro-molecular Med 11, 223-238.
11. Mocchegiani E, Costarelli L, Giacconi R, Cipriano C, Muti E, Malavolta M (2006) Zinc-binding proteins (metalloth-ionein and alpha-2 macroglobulin) and immunosenescence. Exp Gerontol 41, 1094-1107.
12. Carpene E, Andreani G, Isani G (2007) Metallothionein functions and structural characteristics. J Trace Elem Med Biol 21 (Suppl 1), 35-39.
13. Yu X, Guo J, Fang H, Peng S (2011) Basal metallothionein-I/II protects against NMDA-mediated oxidative injury in cortical neuron/astrocyte cultures. Toxicology 282, 16-22.
14. Potter EG, Cheng Y, Knight JB, Gordish-Dressman H, Natale JE (2007) Basic science; metallothionein I and II attenuate the thalamic microglial response following traumatic axotomy in the immature brain. J Neurotrauma 24, 28-42.
15. Miyazaki I, Asanuma M, Hozumi H, Miyoshi K, Sogawa N (2007) Protective effects of metallothionein against dopamine quinone-induced dopaminergic neurotoxicity. FEBS Lett 581, 5003-5008.
16. Uchida Y, Takio K, Titani K, Ihara Y, Tomonaga M (1991) The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein. Neuron 7, 337-347.
17. Carrasco J, Giralt M, Molinero A, Penkowa M, Moos T, Hidalgo J (1999) Metallothionein (MT)-III: Generation of polyclonal antibodies, comparison with MT-I+II in the freeze lesioned rat brain and in a bioassay with astrocytes, and analysis of Alzheimer's disease brains. J Neurotrauma 16, 1115-1129.
18. Yu WH, Lukiw WJ, Bergeron C, Niznik HB, Fraser PE (2001) Metallothionein III is reduced in Alzheimer's disease. Brain Res 894, 37-45.
19. Zatta P (2008) Metallothioneins in biochemistry and pathology, World Scientific Publishing Company.
20. Hozumi I, Suzuki JS, Kanazawa H, Hara A, Saio M, Inuzuka T, Miyairi S, Naganuma A, Tohyama C (2008) Metallothionein-3 is expressed in the brain and various peripheral organs of the rat. Neurosci Lett 438, 54-58.
21. Cyr DG, Dufresne J, Pillet S, Alfieri TJ, Hermo L (2001) Expression and regulation of metallothioneins in the rat epi-didymis. J Androl 22, 124-135.
22. Howells C, West AK, Chung RS (2010) Neuronal growth-inhibitory factor (metallothionein-3): Evaluation of the biological functionof growth-inhibitory factorin the injured and neurodegenerative brain. FEBS J 277, 2931-2939.
23. Belloso E, Hernandez J, Giralt M, Kille P, Hidalgo J (1996) Effect of stress on mouse and rat brain metallothionein I and III mRNA levels. Neuroendocrinology 64, 430-439.
24. Hidalgo J, Belloso E, Hernandez J, Gasull T, Molinero A (1997) Roleofglucocorticoidsonrat brainmetallothionein-I and-III response to stress. Stress 1, 231-240.
25. Hozumi I, Uchida Y, Watabe K, Sakamoto T, Inuzuka T (2006) Growth inhibitory factor (GIF) can protect from brain damage due to stab wounds in rat brain. Neurosci Lett 395, 220-223.
26. Hwang YP, Kim HG, Han EH, Jeong HG (2008) Metallothionein-III protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a PI3K and ERK/Nrf2-dependent manner. Toxicol Appl Pharmacol 231, 318-327.
27. Kim HG, Hwang YP, Jeong HG (2008) Metallothionein-III induces HIF-1alpha-mediated VEGF expression in brain endothelial cells. Biochem Biophys Res Commun 369, 666-671.
28. Carrasco J, Penkowa M, Giralt M, Camats J, Molinero A, Campbell IL, Palmiter RD, Hidalgo J (2003) Role of metallothionein-III following central nervous system damage. Neurobiol Dis 13, 22-36.
29. Erickson JC, Hollopeter G, Thomas SA, Froelick GJ, Palmiter RD (1997) Disruption of the metallothionein-III gene in mice: Analysis of brain zinc, behavior, and neuron vulnerability to metals, aging, and seizures. J Neurosci 17, 1271-1281.
30. Ma F, Wang H, Chen B, Wang F, Xu H (2011) Metalloth-ionein 3 attenuated the apoptosis of neurons in the CA1 region of the hippocampus in the senescence-accelerated mouse/PRONE8 (SAMP8). Arq Neuropsiquiatr 69, 105-111.
31. Chung RS, Vickers JC, Chuah MI, Eckhardt BL, West AK (2002) Metallothionein-III inhibits initial neurite formation in developing neurons as well as postinjury, regenerative neurite sprouting. Exp Neurol 178, 1-12.
32. Rossipal E, Krachler M (2008) Studies of the placenta and mammary glandtransferoftraceelement: Impactofpossible trace element deficiencies in infancy. Cell Biol Toxicol 24, 371-374.
33. Holloway AF, Stennard FA, Dziegielewska KM, Weller L, West AK (1997) Localisation and expression of metalloth-ionein immunoreactivity in the developing sheep brain. Int J Dev Neurosci 15, 195-203.
34. Cozzi B, Giacomello M, Zambenedetti P, Bolognin S, Rossipal E, Peruffo A, Zatta P (2010) Ontogenesis and migration of metallothionein I/II-containing glial cells in the human telencephalon during the second trimester. Brain Res 1327, 16-23.
35. Sancho-Tello M, Valles S, Montoliu C, Renau-Piqueras J, Guerri C (1995) Developmental pattern of GFAP and vimentin gene expression in rat brain and in radial glial cultures. Glia 15, 157-166.
36. Bruni JE (1998) Ependymal development, proliferation, and functions: A review. Microsc Res Tech 41, 2-13.
37. Bystron I, Blakemore C, Rakic P (2008) Development of the human cerebral cortex: Boulder Committee revisited. Nat Rev Neurosci 9, 110-122.
38. Choudhuri S, Liu WL, Berman NE, Klaassen CD (1996) Cadmium accumulation and metallothionein expression in brainofmice atdifferent stages ofdevelopment. Toxicol Lett 84, 127-133.
39. Eisen A (2009) Amyotrophic lateral sclerosis: A 40-year personal perspective. J Clin Neurosci 16, 505-512.
40. Cozzolino M, Ferri A, Carri MT (2008) Amyotrophic lateral sclerosis: From current developments in the laboratory to clinical implications. Antioxid Redox Signal 10, 405-443.
41. Morahan JM, Pamphlett R (2006) Amyotrophic lateral sclerosis and exposure to environmental toxins: An Australian case-control study. Neuroepidemiology 27, 130-135.
42. Morahan JM, Yu B, Trent RJ, Pamphlett R (2007) Are met-allothionein genes silencedin ALS? Toxicol Lett168, 83-87.
43. Hayashi Y, Hashizume T, Wakida K, Satoh M, Uchida Y, Watabe K, Matsuyama Z, Kimura A, Inuzuka T, Hozumi I (2006) Association between metallothionein genes polymorphisms and sporadic amyotrophic lateral sclerosis in a Japanese population. Amyotroph Lateral Scler 7, 22-26.
44. Seetharaman SV, Prudencio M, Karch C, Holloway SP, Borchelt DR, Hart PJ (2009) Immature copper-zinc superoxide dismutase and familial amyotrophic lateral sclerosis. Exp Biol Med (Maywood) 234, 1140-1154.
45. Crow JP, Sampson JB, Zhuang Y, Thompson JA, Beckman JS (1997) Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite. J Neurochem 69, 1936-1944.
46. Lyons TJ, Liu H, Goto JJ, Nersissian A, Roe JA, Graden JA, Cafe C, Ellerby LM, Bredesen DE, Gralla EB, Valentine JS (1996) Mutations in copper-zinc superoxide dismutase that cause amyotrophic lateral sclerosis alter the zinc binding site and the redox behavior of the protein. Proc Natl Acad Sci USA 93, 12240-12244.
47. Estevez AG, Crow JP, Sampson JB, Reiter C, Zhuang Y, Richardson GJ, Tarpey MM, Barbeito L, Beckman JS (1999) Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science 286, 2498-2500.
48. Said Ahmed M, Hung WY, Zu JS, Hockberger P, Siddique T (2000) Increased reactive oxygen species in familial amy-otrophic lateral sclerosis with mutations in SOD1. J Neurol Sci 176, 88-94.
49. Hozumi I, Yamada M, Uchida Y, Ozawa K, Takahashi H, Inuzuka T (2008) The expression of metallothioneins is diminishedinthe spinal cordsofpatientswithsporadic ALS. Amyotroph Lateral Scler 9, 294-298.
50. Tokuda E, Ono S, Ishige K, Naganuma A, Ito Y, Suzuki T (2007) Metallothionein proteins expression, copper and zinc concentrations, and lipid peroxidation level in a rodent model for amyotrophic lateral sclerosis. Toxicology 229, 33-41.
51. Ono S, Endo Y, Tokuda E, Ishige K, Tabata K, Asami S, Ito Y, Suzuki T (2006) Upregulation of metallothionein-I mRNA expression in a rodent model for amyotrophic lateral sclerosis. Biol Trace Elem Res 113, 93-104.
52. Przedborski S, Donaldson DM, Murphy PL, Hirsch O, Lange D, Naini AB, McKenna-Yasek D, Brown RH Jr (1996) Blood superoxide dismutase, catalase and glu-tathione peroxidase activities in familial and sporadic amyotrophic lateral sclerosis. Neurodegeneration 5, 57-64.
53. Sillevis Smitt PA, Mulder TP, Verspaget HW, Blaauwgeers HG, Troost D, de Jong JM (1994) Metallothionein in amy-otrophic lateral sclerosis. Biol Signals 3, 193-197.
54. Iqbal K, Liu F, Gong CX, Alonso Adel C, Grundke-Iqbal I (2009) Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 118, 53-69.
55. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 8, 101-112.
56. Roberts BR, Ryan TM, Bush AI, Masters CL, Duce JA (2012) The role of metallobiology and amyloid-beta pep-tides in Alzheimer's disease. J Neurochem 120 (Suppl 1), 149-166.
57. Miu AC, Benga O (2006) Aluminum and Alzheimer's disease: A new look. J Alzheimers Dis 10, 179-201.
58. Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR (1998) Copper, iron and zinc in Alzheimer's disease senile plaques. J Neurol Sci 158, 47-52.
59. Bush AI, Tanzi RE (2008) Therapeutics for Alzheimer's disease based on the metal hypothesis. Neurotherapeutics 5, 421-432.
60. Arnal N, Cristalli DO, de Alaniz MJ, Marra CA (2010) Clinical utility of copper, ceruloplasmin, and metallothionein plasma determinations in human neurodegenerative patients and their first-degree relatives. Brain Res 1319, 118-130.
61. Zambenedetti P, Giordano R, Zatta P (1998) Met-allothioneins are highly expressed in astrocytes and microcapillaries in Alzheimer's disease. J Chem Neuroanat 15, 21-26.
62. Adlard PA, West AK, Vickers JC (1998) Increased density of metallothionein I/II-immunopositive cortical glial cells in the early stages of Alzheimer's disease. Neurobiol Dis 5, 349-356.
63. Chuah MI, Getchell ML (1999) Metallothionein in olfactory mucosa of Alzheimer's disease patients and apoE-deficient mice. Neuroreport 10, 1919-1924.
64. Barnham KJ, Haeffner F, Ciccotosto GD, Curtain CC, Tew D, Mavros C, Beyreuther K, Carrington D, Masters CL, Cherny RA, Cappai R, Bush AI (2004) Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer's disease beta-amyloid. FASEB J 18, 1427-1429.
65. Streit WJ (2004) Microglia and Alzheimer's disease patho-genesis. J Neurosci Res 77, 1-8.
66. Kim JH, Nam YP, Jeon SM, Han HS, Suk K (2012) Amyloid neurotoxicity is attenuated by metallothionein: Dual mechanisms at work. J Neurochem 121, 751-762.
67. Manso Y, Adlard PA, Carrasco J, Vasak M, Hidalgo J (2011) Metallothionein and brain inflammation. J Biol Inorg Chem 16, 1103-1113.
68. Manso Y, Carrasco J, Comes G, Adlard PA, Bush AI, Hidalgo J (2012) Characterization of the role of the antiox-idant proteins metallothioneins 1 and 2 in an animal model of Alzheimer's disease. Cell Mol Life Sci 69, 3665-3681.
69. Naruse S, Igarashi S, Furuya T, Kobayashi H, Miyatake T, Tsuji S (1994) Structures of the human and mouse growth inhibitory factor-encoding genes. Gene 144, 283-287.
70. El Ghazi I, Martin BL, Armitage IM (2006) Metallothionein-3 is a component of a multiprotein complex in the mouse brain. Exp Biol Med (Maywood) 231, 1500-1506.
71. Martin BL, Tokheim AM, McCarthy PT, Doms BS, Davis AA, Armitage IM (2006) Metallothionein-3 and neuronal nitric oxide synthase levelsinbrains from the Tg2576 mouse model of Alzheimer's disease. Mol Cell Biochem 283, 129-137.
72. Amoureux MC, Van Gool D, Herrero MT, Dom R, Colpaert FC, Pauwels PJ (1997) Regulation of metallothionein-III (GIF) mRNA in the brain of patients with Alzheimer disease is not impaired. Mol Chem Neuropathol 32, 101-121.
73. Erickson JC, Sewell AK, Jensen LT, Winge DR, Palmiter RD (1994) Enhanced neurotrophic activity in Alzheimer's disease cortex is not associated with down-regulation of metallothionein-III (GIF). Brain Res 649, 297-304.
74. Hidalgo J, Penkowa M, Espejo C, Martinez-Caceres EM, Carrasco J, Quintana A, Molinero A, Florit S, Giralt M, Ortega-Aznar A (2006) Expression of metallothionein-I,-II, and-III in Alzheimer disease and animal models of neuroin-flammation. Exp Biol Med (Maywood) 231, 1450-1458.
75. Esiri MM, Wilcock GK, Morris JH (1997) Neuropatholog-ical assessment of the lesions of significance in vascular dementia. J Neurol Neurosurg Psychiatry 63, 749-753.
76. Tanoi Y, Okeda R, Budka H (2000) Binswanger's encephalopathy: Serial sections and morphometry of the cerebral arteries. Acta Neuropathol 100, 347-355.
77. Pantoni L, Garcia JH, Gutierrez JA (1996) Cerebral white matter is highly vulnerable to ischemia. Stroke 27, 1641-1646; discussion 1647.
78. Zambenedetti P, Schmitt HP, Zatta P (2002) Metalloth-ionein I-II immunocytochemical reactivity in Binswanger's encephalopathy. J Alzheimers Dis 4, 459-466.
79. Tohgi H, Sasaki K, Chiba K, Nozaki Y (1990) Effect of vinpocetine on oxygen release of hemoglobin and ery-throcyte organic polyphosphate concentrations in patients with vascular dementia of the Binswanger type. Arzneimit-telforschung 40, 640-643.
80. Takahashi S, Abe T, Tohgi H (1996) [Problems in vascular dementia]. Nihon Ronen Igakkai Zasshi 33, 158-163.
81. Masumura M, Hata R, Akatsu H, Kosaka K, Yamamoto T, Nagai Y, Sawada T (2001) Increasing in situ nick end labelingof oligodendrocytes inwhite matter of patients with Binswanger's disease. J Stroke Cerebrovasc Dis 10, 55-62.
82. Chen CF, Guo SS, Jia HY, Dai JX, Xue SW (1996) The role of endothelin-1 in Binswanger's disease. Zhonghua Yi Xue Za Zhi (Taipei) 58, 151-155.
83. Kaji T, Yamamoto C, Tsubaki S, Ohkawara S, Sakamoto M, Sato M, Kozuka H (1993) Metallothionein induction by cadmium, cytokines, thrombin and endothelin-1 in cultured vascular endothelial cells. Life Sci 53, 1185-1191.
84. Rasia RM, Bertoncini CW, Marsh D, Hoyer W, Cherny D, Zweckstetter M, Griesinger C, Jovin TM, Fernandez CO (2005) Structural characterization of copper (II) binding to alpha-synuclein: Insights into the bioinorganic chemistry of Parkinson's disease. Proc Natl Acad Sci USA 102, 4294-4299.
85. Mirza B, Hadberg H, Thomsen P, Moos T (2000) The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson's disease. Neuroscience 95, 425-432.
86. Zhang Y, James M, Middleton FA, Davis RL (2005) Tran-scriptional analysis of multiple brain regions in Parkinson's disease supports the involvement of specific protein processing, energy metabolism, and signaling pathways, and suggests novel disease mechanisms. Am J Med Genet B Neuropsychiatr Genet 137B, 5-16.
87. Michael GJ, Esmailzadeh S, Moran LB, Christian L, Pearce RK, Graeber MB (2011) Up-regulation of metallothionein gene expression in Parkinsonian astrocytes. Neurogenetics 12, 295-305.
88. Ebadi M, Brown-Borg H, El Refaey H, Singh BB, Garrett S, Shavali S, Sharma SK (2005) Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease. Brain Res Mol Brain Res 134, 67-75.
89. Ebadi M, Sharma S (2006) Metallothioneins 1 and 2 attenuate peroxynitrite-induced oxidative stress in Parkinson disease. Exp Biol Med (Maywood) 231, 1576-1583.
90. Sharma SK, Ebadi M (2003) Metallothionein attenuates 3- morpholinosydnonimine (SIN-1)-induced oxidative stress in dopaminergic neurons. Antioxid Redox Signal 5, 251-264.
91. Cai L, Klein JB, Kang YJ (2000) Metallothionein inhibits peroxynitrite-induced DNA and lipoprotein damage. J Biol Chem 275, 38957-38960.
92. McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38, 1285-1291.
93. Mogi M, Harada M, Narabayashi H, Inagaki H, Minami M, Nagatsu T (1996) Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson's disease. Neurosci Lett 211, 13-16.
94. Banati RB, Daniel SE, Blunt SB (1998) Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease. Mov Disord 13, 221-227.
95. Eibl JK, Abdallah Z, Ross GM (2010) Zinc-metallothionein: A potential mediator of antioxidant defence mechanisms in response to dopamine-induced stress. Can J Physiol Pharmacol 88, 305-312.
96. Sato M, Bremner I (1993) Oxygen free radicals and metal-lothionein. Free Radic Biol Med 14, 325-337.
97. Bray TM, Bettger WJ (1990) The physiological role of zinc as an antioxidant. Free Radic Biol Med 8, 281-291.
98. Forsleff L, Schauss AG, Bier ID, Stuart S (1999) Evidence of functional zinc deficiency in Parkinson's disease. J Altern Complement Med 5, 57-64.
99. Jimenez-Jimenez FJ, Molina JA, Aguilar MV, Meseguer I, Mateos-Vega CJ, Gonzalez-Munoz MJ, de Bustos F, Martinez-Salio A, Orti-Pareja M, Zurdo M, Martinez-Para MC (1998) Cerebrospinal fluid levels of transition metals in patients with Parkinson's disease. J Neural Transm 105, 497-505.
100. Miyazaki I, Sogawa CA, Asanuma M, Higashi Y, Tanaka KI, Nakanishi T, Ogawa N (2000) Expression of metallothionein-III mRNA and its regulation by levodopa in the basal ganglia of hemi-parkinsonian rats. Neurosci Lett 293, 65-68.
101. Lee JY, Kim JH, Palmiter RD, Koh JY (2003) Zinc released from metallothionein-iii may contribute to hippocampal CA1 and thalamic neuronal death following acute brain injury. Exp Neurol 184, 337-347.
102. Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95, 13363-13383.
103. Singh A, Kong Q, Luo X, Petersen RB, Meyerson H, Singh N (2009) Prion protein (PrP) knock-out mice show altered iron metabolism: A functional role for PrP in iron uptake and transport. PLoS One 4, e6115.
104. Stys PK, You H, Zamponi GW (2012) Copper-dependent regulation of NMDA receptors by cellular prion protein: Implications for neurodegenerative disorders. J Physiol 590, 1357-1368.
105. Dandoy-Dron F, Guillo F, Benboudjema L, Deslys JP, Las-mezas C, Dormont D, Tovey MG, Dron M (1998) Gene expression in scrapie. Cloning of a new scrapie-responsive gene and the identification of increased levels of seven other mRNA transcripts. J Biol Chem 273, 7691-7697.
106. Tortosa R, Vidal E, Costa C, Alamillo E, Torres JM, Ferrer I, Pumarola M (2008) Stress response in the central nervous system of a transgenic mouse model of bovine spongiform encephalopathy. Ve t J 178, 126-129.
107. Hanlon J, Monks E, Hughes C, Weavers E, Rogers M (2002) Metallothionein in bovine spongiform encephalopa-thy. J Comp Pathol 127, 280-289.
108. Kawashima T, Doh-ura K, Torisu M, Uchida Y, Furuta A, Iwaki T (2000) Differential expression of metallothioneins in human prion diseases. Dement Geriatr Cogn Disord 11, 251-262.
109. Rezaie P, Lantos PL (2001) Microglia and the pathogenesis of spongiform encephalopathies. Brain Res Brain Res Rev 35, 55-72.
110. Rezaie P, Al-Sarraj S (2007) Vacuolar degeneration affecting brain macrophages/microglia in variant CJD: A report on two cases. Acta Neuropathol 114, 651-658.
111. Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, von Bohlen A, Schulz-Schaeffer W, Giese A, Westaway D, Kretzschmar H (1997) The cellular prion protein binds copper in vivo. Nature 390, 684-687.
112. Miura T, Hori-i A, Takeuchi H (1996) Metal-dependent alpha-helix formation promoted by the glycine-rich octapeptide regionofprion protein. FEBS Lett396, 248-252.
113. Pattison IH, Jebbett JN (1971) Histopathological similarities between scrapie and cuprizone toxicity in mice. Nature 230, 115-117.
114. Zatta P, Raso M, Zambenedetti P, Wittkowski W, Messori L, Piccioli F, Mauri PL, Beltramini M (2005) Copper and zinc dismetabolism in the mouse brain upon chronic cuprizone treatment. Cell Mol Life Sci 62, 1502-1513.
115. Brown DR (1999) Prion protein expression aids cellular uptake and veratridine-induced releaseofcopper. J Neurosci Res 58, 717-725.
116. Varela-Nallar L, Toledo EM, Larrondo LF, Cabral AL, Martins VR, Inestrosa NC (2006) Induction of cellular prion protein gene expression by copper in neurons. Am J Physiol Cell Physiol 290, C271-C281.
117. Yu S, Yin S, Pham N, Wong P, Kang SC, Petersen RB, Li C, Sy MS (2008) Ligand binding promotes prion protein aggregation-role of the octapeptide repeats. FEBS J 275, 5564-5575.
118. Wong BS, Chen SG, Colucci M, Xie Z, Pan T, Liu T, Li R, Gambetti P, Sy MS, Brown DR (2001) Aberrant metal binding by prion protein in human prion disease. J Neurochem 78, 1400-1408.
119. West AK, Chuah MI, Vickers JC, Chung RS (2004) Protective role of metallothioneins in the injured mammalian brain. Rev Neurosci 15, 157-166.
120. Vasak M (2005) Advances in metallothionein structure and functions. J Trace Elem Med Biol 19, 13-17.
121. Chung RS, Hidalgo J, West AK (2008) New insight into the molecular pathways of metallothionein-mediated neuropro-tection and regeneration. J Neurochem 104, 14-20.
122. Bonda DJ, Wang X, Perry G, Nunomura A, Tabaton M, Zhu X, Smith MA (2010) Oxidative stress in Alzheimer disease: A possibility for prevention. Neuropharmacology 59, 290-294.
123. Perfeito R, Cunha-Oliveira T, Rego AC (2012) Revisiting oxidative stress and mitochondrial dysfunction in the patho-genesis of Parkinson disease-resemblance to the effect of amphetamine drugsofabuse. Free Radic Biol Med 53, 1791-1806.
124. Sato M, Kawakami T, Kondoh M, Takiguchi M, Kadota Y, Himeno S, Suzuki S (2010) Development of high-fat-diet-inducedobesityinfemale metallothionein- nullmice. FASEB J 24, 2375-2384.
125. Yang X, Doser TA, Fang CX, Nunn JM, Janardhanan R, Zhu M, Sreejayan N, Quinn MT, Ren J (2006) Metallothionein prolongs survival and antagonizes senescence-associated cardiomyocyte diastolic dysfunction: Role of oxidative stress. FASEB J 20, 1024-1026.
126. Malavolta M, Basso A, Piacenza F, Giacconi R, Costarelli L, Pierpaoli S, Mocchegiani E (2012) Survival study of metallothionein-1 transgenic mice and respective controls (C57BL/6J): Influence of a zinc-enriched environment. Rejuvenation Res 15, 140-143.
127. Cipriano C, Malavolta M, Costarelli L, Giacconi R, Muti E, Gasparini N, Cardelli M, Monti D, Mariani E, Mocchegiani E (2006) Polymorphisms in MT1a gene coding region are associated with longevity in Italian Central female population. Biogerontology 7, 357-365.
128. Nadon NL, Strong R, Miller RA, Nelson J, Javors M, Sharp ZD, Peralba JM, Harrison DE (2008) Design of aging intervention studies: The NIA interventions testing program. Age (Dordr) 30, 187-199.
129. Lanza C, Raimondo S, Vergani L, Catena N, Senes F, Tos P, Geuna S (2012) Expression of antioxidant molecules after peripheral nerve injury and regeneration. J Neurosci Res 90, 842-848.
130. Chung RS, Vickers JC, Chuah MI, West AK (2003) Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury. J Neurosci 23, 3336-3342.
131. Ceballos D, Lago N, Verdu E, Penkowa M, Carrasco J, Navarro X, Palmiter RD, Hidalgo J (2003) Role of met-allothioneins in peripheral nerve function and regeneration. Cell Mol Life Sci 60, 1209-1216.
132. West AK, Leung JY, Chung RS (2011) Neuroprotec-tion and regeneration by extracellular metallothionein via lipoprotein-receptor-related proteins. J Biol Inorg Chem 16, 1115-1122.
133. Lewis KE, Chung RS, West AK, Chuah MI (2012) Distribution of exogenous metallothionein following intraperitoneal and intramuscular injection of metallothionein-deficient mice. Histol Histopathol 27, 1459-1470.
134. Ambjorn M, Asmussen JW, Lindstam M, Gotfryd K, Jacob-sen C, Kiselyov VV, Moestrup SK, Penkowa M, Bock E, Berezin V (2008) Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family. J Neurochem 104, 21-37.
135. Sonn K, Pankratova S, Korshunova I, Zharkovsky A, Bock E, Berezin V, Kiryushko D (2010) A metalloth-ionein mimetic peptide protects neurons against kainic acid-induced excitotoxicity. J Neurosci Res 88, 1074-1082.
136. Lelievre EC, Plestant C, Boscher C, Wolff E, Mege RM, Birbes H (2012) N-cadherin mediates neuronal cell survival through Bim down-regulation. PLoS One 7, e33206.
137. Trayhurn P, Duncan JS, Wood AM, Beattie JH (2000) Regulation of metallothionein gene expression and secretion in rat adipocytes differentiated from preadipocytes in primary culture. Horm Metab Res 32, 542-547.
138. Uchida Y, Gomi F, Masumizu T, Miura Y (2002) Growth inhibitory factor prevents neurite extension and the death of cortical neurons caused by high oxygen exposure through hydroxyl radical scavenging. J Biol Chem 277, 32353-32359.
139. El Ghazi I, Martin BL, Armitage IM (2010) New proteins found interacting with brain metallothionein-3 are linked to secretion. Int J Alzheimers Dis 2011, 208634.
140. Hao Q, Hong SH, Maret W (2007) Lipid raft-dependent endocytosis of metallothionein in HepG2 cells. J Cell Physiol 210, 428-435.
141. Giralt M, Penkowa M, Lago N, Molinero A, Hidalgo J (2002) Metallothionein-1+2 protect the CNS after a focal brain injury. Exp Neurol 173, 114-128.
142. Chung RS, West AK (2004) A role for extracellular met-allothioneins in CNS injury and repair. Neuroscience 123, 595-599.
143. Zatta P, Raso M, Zambenedetti P, Rocco P, Petretto A, Mauri P, Cozzi B (2006) Metallothionein-I-II expression in young and adult bovine pineal gland. J Chem Neuroanat 31, 124-129.
144. Mocchegiani E, Giacconi R, Muti E, Rogo C, Bracci M, Muzzioli M, Cipriano C, Malavolta M (2004) Zinc, immune plasticity, aging, and successful aging: Role of metalloth-ionein. Ann N Y Acad Sci 1019, 127-134.
145. Lee WW, Cui D, Czesnikiewicz-Guzik M, Vencio RZ, Shmulevich I, Aderem A, Weyand CM, Goronzy JJ (2008) Age-dependent signature of metallothionein expression in primary CD4 T cell responses is due to sustained zinc signaling. Rejuvenation Res 11, 1001-1011.