Copper is a transition metal that has been linked to pathological and beneficial effects in neurodegenerative diseases. In Parkinson’s disease, free copper is related to increased oxidative stress, alpha-synuclein oligomerization, and Lewy body formation. Decreased copper along with increased iron has been found in substantia nigra and caudate nucleus of Parkinson’s disease patients. Copper influences iron content in the brain through ferroxidase ceruloplasmin activity; therefore decreased protein-bound copper in brain may enhance iron accumulation and the associated oxidative stress. The function of other copper-binding proteins such as Cu/Zn-SOD and metallothioneins is also beneficial to prevent neurodegeneration. Copper may regulate neurotransmission since it is released after neuronal stimulus and the metal is able to modulate the function of NMDA and GABA A receptors. Some of the proteins involved in copper transport are the transporters CTR1, ATP7A, and ATP7B and the chaperone ATOX1. There is limited information about the role of those biomolecules in the pathophysiology of Parkinson’s disease; for instance, it is known that CTR1 is decreased in substantia nigra pars compacta in Parkinson’s disease and that a mutation in ATP7B could be associated with Parkinson’s disease. Regarding copper-related therapies, copper supplementation can represent a plausible alternative, while copper chelation may even aggravate the pathology. 1. Introduction Parkinson’s disease is an age-associated chronic condition; it is the second most common neurodegenerative disorder, affecting an important fraction of world population. It is estimated that in 2040, in the US alone, the population aged 65 years and older will be as high as 80 million [1]. The costs, at the personal and national health care system levels, continue to rise [1]. The mean age at the onset of Parkinson’s disease is 55 years [2], and its prevalence dramatically increases after this age. Clinically, Parkinson’s disease is characterized by four cardinal symptoms: tremor at rest, muscle rigidity, slowness of movement (bradykinesia, akinesia), and changes in posture (instability). Usually, tremor begins unilaterally and then becomes bilateral [3]. Motor symptoms develop distal, and thus, although tremors in the hands are frequently the first observed, tremors in the face are also common. Walking can be especially difficult for patients; because of the postural instability, patients have a tendency to fall. As a whole, this combination of symptoms leads to disability and dependency. Parkinson’s disease
References
[1]
D. F. Boland and M. Stacy, “The economic and quality of life burden associated with Parkinson's disease: a focus on symptoms,” The American Journal of Managed Care, vol. 18, supplement 7, pp. s168–s175, 2012.
[2]
W. Dauer and S. Przedborski, “Parkinson's disease: mechanisms and models,” Neuron, vol. 39, no. 6, pp. 889–909, 2003.
[3]
J. Jankovic, “Parkinson's disease: clinical features and diagnosis,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 79, no. 4, pp. 368–376, 2008.
[4]
V. W. Sung and A. P. Nicholas, “Nonmotor symptoms in Parkinson's disease: expanding the view of Parkinson's disease beyond a pure motor, pure dopaminergic problem,” Neurologic Clinics, vol. 31, supplement 3, pp. s1–s16, 2013.
[5]
M. Poletti, A. de Rosa, and U. Bonuccelli, “Affective symptoms and cognitive functions in Parkinson's disease,” Journal of the Neurological Sciences, vol. 317, no. 1-2, pp. 97–102, 2012.
[6]
S. Fahn and S. Przedborski, “Parkinsonism,” in Merritt's Neurology, L. P. Rowland and T. A. Pedley, Eds., pp. 751–769, Lippincott Williams & Wilkins, New York, NY, USA, 2010.
[7]
A. B. Singleton, M. J. Farrer, and V. Bonifati, “The genetics of Parkinson's disease: progress and therapeutic implications,” Movement Disorders, vol. 28, no. 1, pp. 14–23, 2013.
[8]
P. Jenner, “Oxidative stress in Parkinson's disease,” Annals of Neurology, vol. 53, supplement 3, pp. S26–s36, 2003.
[9]
U. Wüllner and T. Klockgether, “Inflammation in Parkinson's disease,” Journal of Neurology, vol. 250, suppl. 1, pp. I35–I38, 2003.
[10]
A. H. V. Schapira, “Mitochondrial dysfunction in Parkinson's disease,” Cell Death and Differentiation, vol. 14, no. 7, pp. 1261–1266, 2007.
[11]
S. Rivera-Mancía, I. Pérez-Neri, C. Ríos, et al., “The transition metals copper and iron in neurodegenerative diseases,” Chemico-Biological Interactions, vol. 186, no. 2, pp. 184–189, 2010.
[12]
D. T. Dexter, F. R. Wells, A. J. Lees et al., “Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease,” Journal of Neurochemistry, vol. 52, no. 6, pp. 1830–1836, 1989.
[13]
P. Riederer, E. Sofic, W. D. Rausch et al., “Transition metals, ferritin, glutathione, and ascorbic acid in Parkinsonian brains,” Journal of Neurochemistry, vol. 52, no. 2, pp. 515–520, 1989.
[14]
J. M. Gorell, C. C. Johnson, B. A. Rybicki et al., “Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson's disease,” NeuroToxicology, vol. 20, no. 2-3, pp. 239–247, 1999.
[15]
A. W. Willis, B. A. Evanoff, M. Lian et al., “Metal emissions and urban incident Parkinson disease: a community health study of Medicare beneficiaries by using geographic information systems,” The American Journal of Epidemiology, vol. 172, no. 12, pp. 1357–1363, 2010.
[16]
S. Mariani, M. Ventriglia, I. Simonelli, et al., “Fe and Cu do not differ in Parkinson's disease: a replication study plus meta-analysis,” Neurobiology of Aging, vol. 34, no. 2, pp. 632–633, 2013.
[17]
G. Tórsdóttir, J. Kristinsson, S. Sveinbj？rnsdóttir, et al., “Copper, ceruloplasmin, superoxide dismutase and iron parameters in Parkinson's disease,” Pharmacology and Toxicology, vol. 85, no. 5, pp. 239–243, 1999.
[18]
H. J. Wang, M. Wang, B. Wang et al., “The distribution profile and oxidation states of biometals in APP transgenic mouse brain: dyshomeostasis with age and as a function of the development of Alzheimer's disease,” Metallomics, vol. 4, no. 3, pp. 289–296, 2012.
[19]
H. S. Pall, A. C. Williams, D. R. Blake et al., “Raised cerebrospinal-fluid copper concentration in Parkinson's disease,” The Lancet, vol. 2, no. 8553, pp. 238–241, 1987.
[20]
M. C. Boll, M. Alcaraz-Zubeldia, S. Montes, and C. Rios, “Free copper, ferroxidase and SOD1 activities, lipid peroxidation and NOx content in the CSF. A different marker profile in four neurodegenerative diseases,” Neurochemical Research, vol. 33, no. 9, pp. 1717–1723, 2008.
[21]
I. Hozumi, T. Hasegawa, A. Honda et al., “Patterns of levels of biological metals in CSF differ among neurodegenerative diseases,” Journal of the Neurological Sciences, vol. 303, no. 1-2, pp. 95–99, 2011.
[22]
D. A. Loeffler, P. A. LeWitt, P. L. Juneau et al., “Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders,” Brain Research, vol. 738, no. 2, pp. 265–274, 1996.
[23]
J. R. Prohaska, “Impact of copper limitation on expression and function of multicopper oxidases (ferroxidases),” Advances in Nutrition, vol. 2, pp. 89–95, 2011.
[24]
M. C. Boll, J. Sotelo, E. Otero, M. Alcaraz-Zubeldia, and C. Rios, “Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson's disease,” Neuroscience Letters, vol. 265, no. 3, pp. 155–158, 1999.
[25]
S. Ayton, P. Lei, J. A. Duce, et al., “Ceruloplasmin dysfunction and therapeutic potential for Parkinson's disease,” Annals of Neurology, vol. 73, no. 4, pp. 554–559, 2013.
[26]
D. Hare, S. Ayton, A. Bush, and P. Lei, “A delicate balance: iron metabolism and diseases of the brain,” Frontiers in Aging Neuroscience, vol. 5, article 34, 2013.
[27]
D. Ben-Shachar and M. B. H. Youdim, “Intranigral iron injection induces behavioral and biochemical “Parkinsonism” in rats,” Journal of Neurochemistry, vol. 57, no. 6, pp. 2133–2135, 1991.
[28]
W. A. Spencer, J. Jeyabalan, S. Kichambre, and R. C. Gupta, “Oxidatively generated DNA damage after Cu(II) catalysis of dopamine and related catecholamine neurotransmitters and neurotoxins: role of reactive oxygen species,” Free Radical Biology and Medicine, vol. 50, no. 1, pp. 139–147, 2011.
[29]
D. Ozcelik and H. Uzun, “Copper intoxication; antioxidant defenses and oxidative damage in rat brain,” Biological Trace Element Research, vol. 127, no. 1, pp. 45–52, 2009.
[30]
W. R. Yu, H. Jiang, J. Wang, and J. X. Xie, “Copper (Cu2+) induces degeneration of dopaminergic neurons in the nigrostriatal system of rats,” Neuroscience Bulletin, vol. 24, no. 2, pp. 73–78, 2008.
[31]
C. W. Olanow and P. Brundin, “Parkinson's disease and α synuclein: is Parkinson's disease a prion-like disorder?” Movement Disorders, vol. 28, no. 1, pp. 31–40, 2013.
[32]
V. N. Uversky, J. Li, and A. L. Fink, “Metal-triggered structural transformations, aggregation, and fibrillation of human α-synuclein: a possible molecular link between Parkinson's disease and heavy metal exposure,” The Journal of Biological Chemistry, vol. 276, no. 47, pp. 44284–44296, 2001.
[33]
S. R. Paik, H. J. Shin, J. H. Lee, C. Chang, and J. Kim, “Copper(II)-induced self-oligomerization of α-synuclein,” Biochemical Journal, vol. 340, part 3, pp. 821–828, 1999.
[34]
J. A. Wright, X. Wang, and D. R. Brown, “Unique copper-induced oligomers mediate α-synuclein toxicity,” FASEB Journal, vol. 23, no. 8, pp. 2384–2393, 2009.
[35]
D. L. de Roma？a, M. Olivares, R. Uauy, and M. Araya, “Risks and benefits of copper in light of new insights of copper homeostasis,” Journal of Trace Elements in Medicine and Biology, vol. 25, no. 1, pp. 3–13, 2011.
[36]
E. D. Gaier, B. A. Eipper, and R. E. Mains, “Copper signaling in the mammalian nervous system: synaptic effects,” Journal of Neuroscience Research, vol. 91, no. 1, pp. 2–19, 2013.
[37]
Z. L. Harris and J. D. Gitlin, “Genetic and molecular basis for copper toxicity,” The American Journal of Clinical Nutrition, vol. 63, no. 5, pp. 836S–841S, 1996.
[38]
M. El-Youssef, “Wilson disease,” Mayo Clinic Proceedings, vol. 78, no. 9, pp. 1126–1136, 2003.
[39]
H. Tapiero, D. M. Townsend, and K. D. Tew, “Trace elements in human physiology and pathology. Copper,” Biomedicine and Pharmacotherapy, vol. 57, no. 9, pp. 386–398, 2003.
[40]
M. L. Schlief, A. M. Craig, and J. D. Gitlin, “NMDA receptor activation mediates copper homeostasis in hippocampal neurons,” Journal of Neuroscience, vol. 25, no. 1, pp. 239–246, 2005.
[41]
T. Saito, T. Itoh, M. Fujimura, and K. Saito, “Age-dependent and region-specific differences in the distribution of trace elements in 7 brain regions of Long-Evans Cinnamon (LEC) rats with hereditary abnormal copper metabolism,” Brain Research, vol. 695, no. 2, pp. 240–244, 1995.
[42]
P. Q. Trombley and G. M. Shepherd, “Differential modulation by zinc and copper of amino acid receptors from rat olfactory bulb neurons,” Journal of Neurophysiology, vol. 76, no. 4, pp. 2536–2546, 1996.
[43]
V. Vlachová, H. Zemková, and L. Vyklicky Jr., “Copper modulation of NMDA responses in mouse and rat cultured hippocampal neurons,” European Journal of Neuroscience, vol. 8, no. 11, pp. 2257–2264, 1996.
[44]
T. Weiser and M. Wienrich, “The effects of copper ions on glutamate receptors in cultured rat cortical neurons,” Brain Research, vol. 742, no. 1-2, pp. 211–218, 1996.
[45]
N. L. Salazar-Weber and J. P. Smith, “Copper inhibits NMDA receptor-independent LTP and modulates the paired-pulse ratio after LTP in mouse hippocampal slices,” International Journal of Alzheimer's Disease, vol. 2011, Article ID 864753, 10 pages, 2011.
[46]
C. Peters, B. Mu？oz, F. J. Sepúlveda, et al., “Biphasic effects of copper on neurotransmission in rat hippocampal neurons,” Journal of Neurochemistry, vol. 119, no. 1, pp. 78–88, 2011.
[47]
J. Kardos, I. Kovács, F. Hajós, M. Kalman, and M. Simonyi, “Nerve endings from rat brain tissue release copper upon depolarization. A possible role in regulating neuronal excitability,” Neuroscience Letters, vol. 103, no. 2, pp. 139–144, 1989.
[48]
H. Kim and R. L. Macdonald, “An N-terminal histidine is the primary determinant of α subunit-dependent Cu2+ sensitivity of αβ3γ2L GABAA receptors,” Molecular Pharmacology, vol. 64, no. 5, pp. 1145–1152, 2003.
[49]
T. P. McGee, C. M. Houston, and S. G. Brickley, “Copper block of extrasynaptic GABAA receptors in the mature cerebellum and striatum,” Journal of Neuroscience, vol. 33, no. 33, pp. 13431–13435, 2013.
[50]
M. S. Horning and P. Q. Trombley, “Zinc and copper influence excitability of rat olfactory bulb neurons by multiple mechanisms,” Journal of Neurophysiology, vol. 86, no. 4, pp. 1652–1660, 2001.
[51]
M. G. Spillantini, M. L. Schmidt, V. M.-. Lee, J. Q. Trojanowski, R. Jakes, and M. Goedert, “α-synuclein in Lewy bodies,” Nature, vol. 388, no. 6645, pp. 839–840, 1997.
[52]
O. M. A. El-Agnaf, S. A. Salem, K. E. Paleologou et al., “Detection of oligomeric forms of α-synuclein protein in human plasma as a potential biomarker for Parkinson's disease,” FASEB Journal, vol. 20, no. 3, pp. 419–425, 2006.
[53]
R. Borghi, R. Marchese, A. Negro et al., “Full length α-synuclein is present in cerebrospinal fluid from Parkinson's disease and normal subjects,” Neuroscience Letters, vol. 287, no. 1, pp. 65–67, 2000.
[54]
A. B. Singleton, M. Farrer, J. Johnson et al., “α-synuclein locus triplication causes Parkinson's disease,” Science, vol. 302, no. 5646, p. 841, 2003.
[55]
K. S. P. McNaught, C. W. Olanow, B. Halliwell, O. Isacson, and P. Jenner, “Failure of the ubiquitin-proteasome system in Parkinson's disease,” Nature Reviews Neuroscience, vol. 2, no. 8, pp. 589–594, 2001.
[56]
Y. Tanaka, S. Engelender, S. Igarashi et al., “Inducible expression of mutant α-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis,” Human Molecular Genetics, vol. 10, no. 9, pp. 919–926, 2001.
[57]
R. M. Rasia, C. W. Bertoncini, D. Marsh et al., “Structural characterization of copper(II) binding to α-synuclein: insights into the bioinorganic chemistry of Parkinson's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 12, pp. 4294–4299, 2005.
[58]
C. Wang, L. Liu, L. Zhang, Y. Peng, and F. Zhou, “Redox reactions of the α-synuclein-Cu2+ complex and their effects on neuronal cell viability,” Biochemistry, vol. 49, no. 37, pp. 8134–8142, 2010.
[59]
P. Davies, D. Moualla, and D. R. Brown, “α-synuclein is a cellular ferrireductase,” PLoS ONE, vol. 6, no. 1, Article ID e15814, 2011.
[60]
J. Healy and K. Tipton, “Ceruloplasmin and what it might do,” Journal of Neural Transmission, vol. 114, no. 6, pp. 777–781, 2007.
[61]
M. Sato and J. D. Gitlin, “Mechanisms of copper incorporation during the biosynthesis of human ceruloplasmin,” The Journal of Biological Chemistry, vol. 266, no. 8, pp. 5128–5134, 1991.
[62]
G. Vashchenko and R. T. MacGillivray, “Multi-copper oxidases and human iron metabolism,” Nutrients, vol. 5, no. 7, pp. 2289–2313, 2013.
[63]
B. N. Patel and S. David, “A novel glycosylphosphatidylinositol-anchored form of ceruloplasmin is expressed by mammalian astrocytes,” The Journal of Biological Chemistry, vol. 272, no. 32, pp. 20185–20190, 1997.
[64]
K. Yoshida, K. Furihata, S. Takeda et al., “A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans,” Nature Genetics, vol. 9, no. 3, pp. 267–272, 1995.
[65]
W. R. W. Martin, M. Wieler, and M. Gee, “Midbrain iron content in early Parkinson disease: a potential biomarker of disease status,” Neurology, vol. 70, no. 16, part 2, pp. 1411–1417, 2008.
[66]
D. Berg, C. Siefker, and G. Becker, “Echogenicity of the substantia nigra in Parkinson's disease and its relation to clinical findings,” Journal of Neurology, vol. 248, no. 8, pp. 684–689, 2001.
[67]
L. Zecca, D. Berg, T. Arzberger et al., “In vivo detection of iron and neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage,” Movement Disorders, vol. 20, no. 10, pp. 1278–1285, 2005.
[68]
R. Martínez-Hernández, S. Montes, J. Higuera-Calleja et al., “Plasma ceruloplasmin ferroxidase activity correlates with the nigral sonographic area in Parkinson's disease patients: a pilot study,” Neurochemical Research, vol. 36, no. 11, pp. 2111–2115, 2011.
[69]
L. Jin, J. Wang, L. Zhao et al., “Decreased serum ceruloplasmin levels characteristically aggravate nigral iron deposition in Parkinson's disease,” Brain, vol. 134, no. 1, pp. 50–58, 2011.
[70]
K. J. Bharucha, J. K. Friedman, A. S. Vincent, and E. D. Ross, “Lower serum ceruloplasmin levels correlate with younger age of onset in Parkinson's disease,” Journal of Neurology, vol. 255, no. 12, pp. 1957–1962, 2008.
[71]
S. Olivieri, A. Conti, S. Iannaccone et al., “Ceruloplasmin oxidation, a feature of Parkinson's disease CSF, inhibits ferroxidase activity and promotes cellular iron retention,” Journal of Neuroscience, vol. 31, no. 50, pp. 18568–18577, 2011.
[72]
H. Hochstrasser, P. Bauer, U. Walter et al., “Ceruloplasmin gene variations and substantia nigra hyperechogenicity in Parkinson disease,” Neurology, vol. 63, no. 10, pp. 1912–1917, 2004.
[73]
J. M. McCord and I. Fridovich, “Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein),” The Journal of Biological Chemistry, vol. 244, no. 22, pp. 6049–6055, 1969.
[74]
G. Cohen, “The pathobiology of Parkinson's disease: biochemical aspects of dopamine neuron senescence,” Journal of Neural Transmission. Supplementa, vol. 19, pp. 89–103, 1983.
[75]
S. L. Marklund, “Human copper-containing superoxide dismutase of high molecular weight,” Proceedings of the National Academy of Sciences of the United States of America, vol. 79, no. 24, pp. 7634–7638, 1982.
[76]
S. Przedborski, V. Kostic, V. Jackson-Lewis et al., “Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity,” Journal of Neuroscience, vol. 12, no. 5, pp. 1658–1667, 1992.
[77]
N. Nakao, E. M. Frodl, H. Widner et al., “Overexpressing Cu/Zn superoxide dismutase enhances survival of transplanted neurons in a rat model of Parkinson's disease,” Nature Medicine, vol. 1, no. 3, pp. 226–231, 1995.
[78]
E. Polazzi, I. Mengoni, M. Caprini, et al., “Copper-zinc superoxide dismutase (SOD1) is released by microglial cells and confers neuroprotection against 6-OHDA neurotoxicity,” Neurosignals, vol. 21, no. 1-2, pp. 112–128, 2013.
[79]
K. Takano, N. Tanaka, K. Kawabe, et al., “Extracellular superoxide dismutase induced by dopamine in cultured astrocytes,” Neurochemical Research, vol. 38, no. 1, pp. 32–41, 2013.
[80]
Z. Wang, J. Liu, S. Chen et al., “DJ-1 modulates the expression of Cu/Zn-superoxide dismutase-1 through the Erk1/2-Elk1 pathway in neuroprotection,” Annals of Neurology, vol. 70, no. 4, pp. 591–599, 2011.
[81]
G. M. Earhart and M. J. Falvo, “Parkinson's disease and exercise,” Comprehensive Physiology, vol. 3, no. 2, pp. 833–848, 2013.
[82]
T. Tuon, S. S. Valvassori, J. Lopes-Borges, et al., “Physical training exerts neuroprotective effects in the regulation of neurochemical factors in an animal model of Parkinson's disease,” Neuroscience, vol. 227, pp. 305–312, 2012.
[83]
Y. Ihara, D. Chuda, S. Kuroda, and T. Hayabara, “Hydroxyl radical and superoxide dismutase in blood of patients with Parkinson's disease: relationship to clinical data,” Journal of the Neurological Sciences, vol. 170, no. 2, pp. 90–95, 1999.
[84]
C. Venkateshappa, G. Harish, R. B. Mythri, A. Mahadevan, M. M. Srinivas Bharath, and S. K. Shankar, “Increased oxidative damage and decreased antioxidant function in aging human substantia nigra compared to striatum: implications for Parkinson's disease,” Neurochemical Research, vol. 37, no. 2, pp. 358–369, 2012.
[85]
R. K. Stankovic, R. S. Chung, and M. Penkowa, “Metallothioneins I and II: neuroprotective significance during CNS pathology,” International Journal of Biochemistry and Cell Biology, vol. 39, no. 3, pp. 484–489, 2007.
[86]
M. Va？ák and G. Meloni, “Chemistry and biology of mammalian metallothioneins,” Journal of Biological Inorganic Chemistry, vol. 16, no. 7, pp. 1067–1078, 2011.
[87]
M. Penkowa, M. Cáceres, R. Borup et al., “Novel roles for metallothionein-I + II (MT-I + II) in defense responses, neurogenesis, and tissue restoration after traumatic brain injury: insights from global gene expression profiling in wild-type and MT-I + II knockout mice,” Journal of Neuroscience Research, vol. 84, no. 7, pp. 1452–1474, 2006.
[88]
F. Reinecke, O. Levanets, Y. Olivier et al., “Metallothionein isoform 2A expression is inducible and protects against ROS-mediated cell death in rotenone-treated HeLa cells,” Biochemical Journal, vol. 395, no. 2, pp. 405–415, 2006.
[89]
G. J. Michael, S. Esmailzadeh, L. B. Moran, L. Christian, R. K. B. Pearce, and M. B. Graeber, “Up-regulation of metallothionein gene expression in Parkinsonian astrocytes,” Neurogenetics, vol. 12, no. 4, pp. 295–305, 2011.
[90]
M. Dhanasekaran, C. B. Albano, L. Pellet et al., “Role of lipoamide dehydrogenase and metallothionein on 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine-induced neurotoxicity,” Neurochemical Research, vol. 33, no. 6, pp. 980–984, 2008.
[91]
M. Ebadi and S. Sharma, “Metallothioneins 1 and 2 attenuate peroxynitrite-induced oxidative stress in Parkinson disease,” Experimental Biology and Medicine, vol. 231, no. 9, pp. 1576–1583, 2006.
[92]
G. Meloni and M. Va？ák, “Redox activity of α-synuclein-Cu is silenced by Zn7-metallothionein-3,” Free Radical Biology and Medicine, vol. 50, no. 11, pp. 1471–1479, 2011.
[93]
A. R. White, R. Reyes, J. F. B. Mercer et al., “Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice,” Brain Research, vol. 842, no. 2, pp. 439–444, 1999.
[94]
C. J. Maynard, R. Cappai, I. Volitakis et al., “Overexpression of Alzheimer's disease amyloid-β opposes the age-dependent elevations of brain copper and iron,” The Journal of Biological Chemistry, vol. 277, no. 47, pp. 44670–44676, 2002.
[95]
J. A. Duce, A. Tsatsanis, M. A. Cater et al., “Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease,” Cell, vol. 142, no. 6, pp. 857–867, 2010.
[96]
B. Bj？rkblom, A. Adilbayeva, J. Maple-Gr？dem, et al., “Parkinson's disease protein DJ-1 binds metals and protects against metal-induced cytotoxicity,” The Journal of Biological Chemistry, vol. 288, no. 31, pp. 22809–22820, 2013.
[97]
R. H. Kim, P. D. Smith, H. Aleyasin et al., “Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 14, pp. 5215–5220, 2005.
[98]
M. A. Greenough, I. Volitakis, Q. X. Li et al., “Presenilins promote the cellular uptake of copper and zinc and maintain copper chaperone of SOD1-dependent copper/zinc superoxide dismutase activity,” The Journal of Biological Chemistry, vol. 286, no. 11, pp. 9776–9786, 2011.
[99]
A. Southon, M. A. Greenough, G. Ganio, et al., “Presenilin promotes dietary copper uptake,” PLoS ONE, vol. 8, no. 5, Article ID e62811, 2013.
[100]
E. L. Que, D. W. Domaille, and C. J. Chang, “Metals in neurobiology: probing their chemistry and biology with molecular imaging,” Chemical Reviews, vol. 108, no. 5, pp. 1517–1549, 2008.
[101]
D. R. Brown, K. F. Qin, J. W. Herms et al., “The cellular prion protein binds copperin vivo,” Nature, vol. 390, no. 6661, pp. 684–687, 1997.
[102]
J. Telianidis, Y. H. Hung, S. Materia, and S. L. Fontaine, “Role of the P-type ATPases, ATP7A and ATP7B in brain copper homeostasis,” Frontiers in Aging Neuroscience, vol. 5, article 44, 2013.
[103]
D. L. Huffman and T. V. O'Halloran, “Function, structure, and mechanism of intracellular copper trafficking proteins,” Annual Review of Biochemistry, vol. 70, pp. 677–701, 2001.
[104]
M. C. Linder, Biochemistry of Copper, Plenum Press, New York, NY, USA, 1991.
[105]
B. S. Choi and W. Zheng, “Copper transport to the brain by the blood-brain barrier and blood-CSF barrier,” Brain Research, vol. 1248, pp. 14–21, 2009.
[106]
L. A. Meyer, A. P. Durley, J. R. Prohaska, and Z. L. Harris, “Copper transport and metabolism are normal in aceruloplasminemic mice,” The Journal of Biological Chemistry, vol. 276, no. 39, pp. 36857–36861, 2001.
[107]
A. D. Monnot, M. Behl, S. Ho, and W. Zheng, “Regulation of brain copper homeostasis by the brain barrier systems: effects of Fe-overload and Fe-deficiency,” Toxicology and Applied Pharmacology, vol. 256, no. 3, pp. 249–257, 2011.
[108]
M. Penkowa, H. Nielsen, J. Hidalgo, et al., “Distribution of metallothionein I + II and vesicular zinc in the developing central nervous system: correlative study in the rat,” Journal of Comparative Neurology, vol. 412, no. 2, pp. 303–318, 1999.
[109]
T. Skj？rringe, L. B. M？ller, and T. Moos, “Impairment of interrelated iron- and copper homeostatic mechanisms in brain contributes to the pathogenesis of neurodegenerative disorders,” Frontiers in Pharmacology, vol. 3, article 169, 2012.
[110]
G. Zheng, J. Chen, and W. Zheng, “Relative contribution of CTR1 and DMT1 in copper transport by the blood-CSF barrier: implication in manganese-induced neurotoxicity,” Toxicology and Applied Pharmacology, vol. 260, no. 3, pp. 285–293, 2012.
[111]
E. Gaggelli, H. Kozlowski, D. Valensin, and G. Valensin, “Copper homeostasis and neurodegenerative disorders (Alzheimer's, prion, and Parkinson's diseases and amyotrophic lateral sclerosis),” Chemical Reviews, vol. 106, no. 6, pp. 1995–2044, 2006.
[112]
Y. Kuo, A. A. Gybina, J. W. Pyatskowit, J. Gitschier, and J. R. Prohaska, “Copper transport protein (Ctr1) levels in mice are tissue specific and dependent on copper status,” Journal of Nutrition, vol. 136, no. 1, pp. 21–26, 2006.
[113]
W. Zheng and A. D. Monnot, “Regulation of brain iron and copper homeostasis by brain barrier systems: implication in neurodegenerative diseases,” Pharmacology and Therapeutics, vol. 133, no. 2, pp. 177–188, 2012.
[114]
S. Lutsenko, A. Bhattacharjee, and A. L. Hubbard, “Copper handling machinery of the brain,” Metallomics, vol. 2, no. 9, pp. 596–608, 2010.
[115]
K. M. Davies, D. J. Hare, V. Cottam, et al., “Localization of copper and copper transporters in the human brain,” Metallomics: An Integrated Biometal Science, vol. 5, no. 1, pp. 43–51, 2013.
[116]
S. Bohic, K. Murphy, W. Paulus et al., “Intracellular chemical imaging of the developmental phases of human neuromelanin using synchrotron X-ray microspectroscopy,” Analytical Chemistry, vol. 80, no. 24, pp. 9557–9566, 2008.
[117]
M. J. Petris, K. Smith, J. Lee, and D. J. Thiele, “Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1,” The Journal of Biological Chemistry, vol. 278, no. 11, pp. 9639–9646, 2003.
[118]
K. Davies, S. Bohic, R. Ortega, et al., “Copper pathology in the vulnerable substantia nigra in Parkinson's disease,” Movement Disorders, vol. 28, supplement 1, article 1024, 2013.
[119]
N. C. Mackenzie, M. Brito, A. E. Reyes, and M. L. Allende, “Cloning, expression pattern and essentiality of the high-affinity copper transporter 1 (ctr1) gene in zebrafish,” Gene, vol. 328, no. 1-2, pp. 113–120, 2004.
[120]
V. Tanchou, F. Gas, A. Urvoas et al., “Copper-mediated homo-dimerisation for the HAH1 metallochaperone,” Biochemical and Biophysical Research Communications, vol. 325, no. 2, pp. 388–394, 2004.
[121]
L. W. Klomp, S. J. Lin, D. S. Yuan, R. D. Klausner, V. C. Culotta, and J. D. Gitlin, “Identification and functional expression of HAH1, a novel human gene involved in copper homeostasis,” The Journal of Biological Chemistry, vol. 272, no. 14, pp. 9221–9226, 1997.
[122]
G. S. Naeve, A. M. Vana, J. R. Eggold et al., “Expression profile of the copper homeostasis gene, rAtox1, in the rat brain,” Neuroscience, vol. 93, no. 3, pp. 1179–1187, 1999.
[123]
I. Hamza, J. Prohaska, and J. D. Gitlin, “Essential role for Atox1 in the copper-mediated intracellular trafficking of the Menkes ATPase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 3, pp. 1215–1220, 2003.
[124]
Y. Y. Liu, B. V. Nagpure, P. T. H. Wong, and J. S. Bian, “Hydrogen sulfide protects SH-SY5Y neuronal cells against d-galactose induced cell injury by suppression of advanced glycation end products formation and oxidative stress,” Neurochemistry International, vol. 62, no. 5, pp. 603–609, 2013.
[125]
J. M. Walker, R. Tsivkovskii, and S. Lutsenko, “Metallochaperone Atox1 transfers copper to the NH2-terminal domain of the Wilson's disease protein and regulates its catalytic activity,” The Journal of Biological Chemistry, vol. 277, no. 31, pp. 27953–27959, 2002.
[126]
I. Hamza, A. Faisst, J. Prohaska, J. Chen, P. Gruss, and J. D. Gitlin, “The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 12, pp. 6848–6852, 2001.
[127]
S. Itoh, K. Ozumi, H. W. Kim et al., “Novel mechanism for regulation of extracellular SOD transcription and activity by copper: role of antioxidant-1,” Free Radical Biology and Medicine, vol. 46, no. 1, pp. 95–104, 2009.
[128]
T. Iwase, M. Nishimura, H. Sugimura et al., “Localization of Menkes gene expression in the mouse brain; its association with neurological manifestations in Menkes model mice,” Acta Neuropathologica, vol. 91, no. 5, pp. 482–488, 1996.
[129]
S. G. Kaler and J. P. Schwartz, “Expression of the Menkes disease homolog in rodent neuroglial cells,” Neuroscience Research Communications, vol. 23, no. 1, pp. 61–66, 1998.
[130]
Y. Qian, E. Tiffany-Castiglioni, J. Welsh, and E. D. Harris, “Copper efflux from murine microvascular cells requires expression of the Menkes disease CU-ATPase,” Journal of Nutrition, vol. 128, no. 8, pp. 1276–1282, 1998.
[131]
M. J. Petris, J. F. B. Mercer, J. G. Culvenor, P. Lockhart, P. A. Gleeson, and J. Camakaris, “Ligand-regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking,” EMBO Journal, vol. 15, no. 22, pp. 6084–6095, 1996.
[132]
H. Roelofsen, H. Wolters, M. J. A. van Luyn, N. Miura, F. Kuipers, and R. J. Vonk, “Copper-induced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion,” Gastroenterology, vol. 119, no. 3, pp. 782–793, 2000.
[133]
N. Barnes, R. Tsivkovskii, N. Tsivkovskaia, and S. Lutsenko, “The copper-transporting ATPases, Menkes and Wilson disease proteins, have distinct roles in adult and developing cerebellum,” The Journal of Biological Chemistry, vol. 280, no. 10, pp. 9640–9645, 2005.
[134]
S. Yasmeen, K. Lund, A. de Paepe, et al., “Occipital horn syndrome and classical Menkes syndrome caused by deep intronic mutations, leading to the activation of ATP7A pseudo-exon,” European Journal of Human Genetics, 2013.
[135]
K. H. Weiss, H. Runz, B. Noe et al., “Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease,” Journal of Inherited Metabolic Disease, vol. 33, no. 3, supplement, pp. 233–240, 2010.
[136]
G. Sechi, G. Antonio-Cocco, A. Errigo et al., “Three sisters with very-late-onset major depression and parkinsonism,” Parkinsonism and Related Disorders, vol. 13, no. 2, pp. 122–125, 2007.
[137]
P. C. Bull, G. R. Thomas, J. M. Rommens, J. R. Forbes, and D. W. Cox, “The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene,” Nature Genetics, vol. 5, no. 4, pp. 327–337, 1993.
[138]
S. Johnson, “Is Parkinson's disease the heterozygote form of Wilson's disease: PD？=？1/2 WD?” Medical Hypotheses, vol. 56, no. 2, pp. 171–173, 2001.
[139]
M. Lenartowicz, K. Wieczerzak, W. Krzeptowski et al., “Developmental changes in the expression of the Atp7a gene in the liver of mice during the postnatal period,” Journal of Experimental Zoology A, vol. 313, no. 4, pp. 209–217, 2010.
[140]
K. Terada, T. Nakako, X. Yang et al., “Restoration of holoceruloplasmin synthesis in LEC rat after infusion of recombinant adenovirus bearing WND cDNA,” The Journal of Biological Chemistry, vol. 273, no. 3, pp. 1815–1820, 1998.
[141]
S. Gruenheid, M. Cellier, S. Vidal, and P. Gros, “Identification and characterization of a second mouse Nramp gene,” Genomics, vol. 25, no. 2, pp. 514–525, 1995.
[142]
H. Gunshin, B. Mackenzie, U. V. Berger et al., “Cloning and characterization of a mammalian proton-coupled metal-ion transporter,” Nature, vol. 388, no. 6641, pp. 482–488, 1997.
[143]
X. Wang, G. J. Li, and W. Zheng, “Upregulation of DMT1 expression in choroidal epithelia of the blood-CSF barrier following manganese exposure in vitro,” Brain Research, vol. 1097, no. 1, pp. 1–10, 2006.
[144]
J. Salazar, N. Mena, S. Hunot et al., “Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 47, pp. 18578–18583, 2008.
[145]
Q. He, T. Du, X. Yu, et al., “DMT1 polymorphism and risk of Parkinson's disease,” Neuroscience Letters, vol. 501, no. 3, pp. 128–131, 2011.
[146]
L. W. Hung, V. L. Villemagne, L. Cheng, et al., “The hypoxia imaging agent CuII (atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson's disease,” Journal of Experimental Medicine, vol. 209, no. 4, pp. 837–854, 2012.
[147]
J. A. Obeso, M. C. Rodriguez-Oroz, C. G. Goetz et al., “Missing pieces in the Parkinson's disease puzzle,” Nature Medicine, vol. 16, no. 6, pp. 653–661, 2010.
[148]
M. Rubio-Osornio, S. Montes, F. Pérez-Severiano et al., “Copper reduces striatal protein nitration and tyrosine hydroxylase inactivation induced by MPP+ in rats,” Neurochemistry International, vol. 54, no. 7, pp. 447–451, 2009.
[149]
M. Rubio-Osornio, S. Montes, Y. Heras-Romero, et al., “Induction of ferroxidase enzymatic activity by copper reduces MPP(+)-evoked neurotoxicity in rats,” Neuroscience Research, vol. 75, no. 3, pp. 250–255, 2013.
[150]
P. Rojas, C. Rojas, M. Ebadi, S. Montes, A. Monroy-Noyola, and N. Serrano-García, “EGb761 pretreatment reduces monoamine oxidase activity in mouse corpus striatum during 1-methyl-4-phenylpyridinium neurotoxicity,” Neurochemical Research, vol. 29, no. 7, pp. 1417–1423, 2004.
[151]
P. Rojas, S. Montes, N. Serrano-García, and J. Rojas-Casta？eda, “Effect of EGb761 supplementation on the content of copper in mouse brain in an animal model of Parkinson's disease,” Nutrition, vol. 25, no. 4, pp. 482–485, 2009.
[152]
S. Mandel, O. Weinreb, T. Amit, and M. B. H. Youdim, “Cell signaling pathways in the neuroprotective actions of the green tea polyphenol (-)-epigallocatechin-3-gallate: implications for neurodegenerative diseases,” Journal of Neurochemistry, vol. 88, no. 6, pp. 1555–1569, 2004.
[153]
M. B. H. Youdim, E. Grünblatt, and S. Mandel, “The copper chelator, D-penicillamine, does not attenuate MPTP induced dopamine depletion in mice,” Journal of Neural Transmission, vol. 114, no. 2, pp. 205–209, 2007.
[154]
C. Rios, R. Alvarez-Vega, and P. Rojas, “Depletion of copper and manganese in brain after MPTP treatment of mice,” Pharmacology and Toxicology, vol. 76, no. 6, pp. 348–352, 1995.
[155]
M. Arredondo and M. T. Nú？ez, “Iron and copper metabolism,” Molecular Aspects of Medicine, vol. 26, no. 4-5, pp. 313–327, 2005.
[156]
E. Aigner, I. Theurl, H. Haufe et al., “Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease,” Gastroenterology, vol. 135, no. 2, pp. 680.e1–688.e1, 2008.
[157]
A. Crowe and E. H. Morgan, “Iron and copper interact during their uptake and deposition in the brain and other organs of developing rats exposed to dietary excess of the two metals,” Journal of Nutrition, vol. 126, no. 1, pp. 183–194, 1996.
[158]
R. I. Henkin, S. J. Potolicchio, L. M. Levy, R. Moharram, I. Velicu, and B. M. Martin, “Carbonic anhydrase I, II, and VI, blood plasma, erythrocyte and saliva zinc and copper increase after repetitive transcranial magnetic stimulation,” The American Journal of the Medical Sciences, vol. 339, no. 3, pp. 249–257, 2010.
[159]
E. M. Khedr, J. C. Rothwell, O. A. Shawky, M. A. Ahmed, N. Foly K, and A. Hamdy, “Dopamine levels after repetitive transcranial magnetic stimulation of motor cortex in patients with Parkinson's disease: preliminary results,” Movement Disorders, vol. 22, no. 7, pp. 1046–1050, 2007.
[160]
B. K. Randhawa, B. G. Farley, and L. A. Boyd, “Repetitive transcranial magnetic stimulation improves handwriting in Parkinson's disease,” Parkinson's Disease, vol. 2013, Article ID 751925, 9 pages, 2013.
[161]
A. P. Strafella, J. H. Ko, J. Grant, M. Fraraccio, and O. Monchi, “Corticostriatal functional interactions in Parkinson's disease: a rTMS/[11C]raclopride PET study,” European Journal of Neuroscience, vol. 22, no. 11, pp. 2946–2952, 2005.
