Iron Transport and Uptake

Supplementary Table 1. Homeostatic Machinery Of Iron Metabolism With A Link To Alzheimer’s Disease And Other Associated Disorders Protein

Protein abbreviation

Gene

Function in Iron Metabolism

Link with Alzheimer's Disease

Human Disorders of Iron Metabolism

Ref

Iron Transport and Uptake

Transferrin

Exocyst complex component 6

Lactotransferrin

Transferrin Receptor 1

Divalent metal-ion transporter-1 Zrt- and Irt-like protein 14 Natural resistance-associated macrophage protein 1 Lipocalin-2

Tf

Sec15l1

LTF

TfR1

DMT1 ZIP14 NRAMP1 LCN2

Six transmembrane epithelial antigen of prostate protein 3 Duodenal cytochrome B

Steap3

Scavenger receptor class A member 5

Scara5

T-cell Ig domain and mucin domain protein-2

TIM-2

DCYTB

Tf (3q22.1)

Plasma, CSF and Lymph Iron (Fe3+) transport

EXOC6 (10q23.33)

Facilitating Tf-cycling

LTF (3p21.31)

Fe-binding glycoprotein

TfRC (3q29)

Endocytic pathway of Iron Uptake

SLC11A2 (12q13) SLC39A14 (8p21.3)

Ferrous iron importer

SLC11A1 (2q35) LCN2 (9q34) Steap3 (2q14.2) CYBRD1 (2q31.1) Scara5 (8p21.1) Tim-2

• AD individuals seems to carry Tf variant C2 highlighting the significance of free radical damage[1] • Higher risk of AD for individuals with elevated Tf-saturations and cholesterol levels[2] • Combinatory effect of C2 allele of transferrin and the C282Y allele of the HFE gene induce severe oxidative stress in neurons[3] • Transferrin saturates in AD patients[4] Unknown

Hereditary atransferrinemia

[5]

Unknown [6, 7]

• Lf is highly up-regulated in cortex area of AD brain and that is shown to be due to microglia and monocytes/macrophages infiltrating from the circulation[8] • Altered TfR density in AD brain[11] • Speculation on the role of TfR in Aluminum association in the AD neuropathology[12] No major effect[13]

Mediator of non-transferrin bound iron uptake in hepatocytes and enterocytes Phagosomal iron transport in macrophages Binds Bacterial siderophore and delivers it to mammalian cells Endosomal ferrireductase

Unknown

Intestinal ferrireductase

Unknown

L-ferritin receptor

Unknown (?) (The Scara1 member is shown to facilitate Aβ clearance[24]) Unknown

H-ferritin receptor

Iron Deficiency Anemia

[9, 10]

Anemia [5] Iron overload in liver; anemia Unknown

[14] [15-18]

No major effect

Hepatic Iron Over load

Unknown

Unknown

[14] [19, 20]

Unknown

Hypochromic, microcytic anemia No overt defect

[21, 22] [14, 23]

Unknown [25] No overt abnormalities

[26]

Transient receptor potential mucolipidosis-associated protein Feline leukemia virus subgroup C receptor 2 CD163

TRPML1 FLVCR2 CD163

Low-density lipoprotein receptor-related protein 1

LRP1 / CD91

Heme carrier protein1/Proton-coupled folate transporter Glucose transporter-1

HCP1/PCFT

Hemopexin Haptoglobin

Heme oxygenase 1

Heme oxygenase 2

Glut-1

HPX HP

HO-1

HO-2

Ferritin H chain

HFT

Ferritin L chain

LFT

TRPML1 (19p13.2)

Endo/lysosomal iron transporter

Proposed to be involved in Ca2+ dyshomeostasis in AD pathobiology[27, 28]

Mucolipidosis type IV

FLVCR2 (14q24.3) CD163 (12p13.3)

Heme Importer

Unknown

Fowler Syndrome

Receptor for Hb/Haptoglobin (HP) complex (Macrophage and Monocyte Iron Uptake) Receptor for HemeHemopexin complex (Macrophage iron uptake) Low affinity heme importer/high-affinity folate transporter Involved in non-transferrin bounded iron uptake; Facilitator of Transplasma membrane electron transport system

Unknown

Unknown

Involved in Amyloidogenic pathway[34] and LOAD[35]

Alzheimer's Disease

Unknown

Hereditary Folate Malabsorption

LRP1 (12q13-q14) SLC46A1 (17q11.2) SLc2a1 (1p34.2)

HPX (11p15.5-p15.4) HP (16q22.2)

HMOX1 (22q13.1)

HMOX2 (16p13.3)

FTH1 (11q13) FTL (19q13.33)

Poly (rC)- binding protein-1

PCBP1

PCBP1 (2p13-p12)

Ferroportin 1

FPN1

SLC40A1 (2q32)

GLUT-1 is significantly reduced in BBB of AD[38-40]

[30] [31-33] [33]

[36, 37]

GLUT1 deficiency syndrome, anemia [41]

Iron Scavenging and Recycling Machinery Scavenging and clearing Heme shown to interact with β-amyloid[42] Heme Scavenging and clearing Hemoglobin (i.e. Hemoglobin chaperone)

[29]

• Increased in AD CSF[44, 45] • Potential biomarker to discriminate AD and other dementias[46]

• Potential Biomarkerof AD[49] • Promotes mitochondrial dysfunction in neuroglia and induction of NFT[50] • No genetic association in AD[51] Recycling of Iron from heme • Potential antioxidative properties in in Enterocytes brain[54] • No genetic association in AD[51] Iron Storage Machinery Intracellular Iron Storage; Decreased in AD[55] ferroxidase activity Intracellular Iron Storage Involved in a neurodegenerative disease characterized with cognitive declines[58] Recycling of Iron from hemoglobin in macrophages

Cytoplasmic Chaperone to Unknown load iron into Ferritin Iron Export Machinery Ferrous Exporter Unknown

Heme-induced inflammation, hemolytic anemia

Hemolytic anemia

[43]

[47, 48]

Anemia [52, 53] Unknown [43]

Iron Overload, Autosomal Dominant Hyperferritinemiacataract syndrome, Neuroferritinopathy Unknown

FPN-related hemochromatosis (Type 4)

[56, 57] [57, 59, 60] [61]

[62, 63]

Ceroluplasmin

MON1A Hephaestin

CP

MON1A HEPH

Hereditary aceruloplasminemia, microcytic anemia

Ferroportin Trafficking

• Neuroprotection against redox-active iron[64] • Increased in AD CSF[65] • Decreased activity in AD CSF[66] • CP fragmentation in AD serum[67] Unknown

Gut and CNS ferroxidase

Unknown

Hereditary hemochromatosis, Hypochromic, microcytic anemia Alzheimer's Disease

CP (3q23-q25)

Secreted Ferrous Oxidase

Mon1a (3p21.31) HEPH (Xq11-q12)

Amyloid β precursor protein

APP

APP (21q21.3)

CNS ferroxidase, (regulated by Iron[74])

• Precursor of β-amyloid[75] • Amyloidogenic pathway[76]

Feline leukemia virus, type C, receptor-1

FLVCR1

FLVCR1 (1q32.3)

Heme Exporter

Unknown

Mitoferrin-1 (erythroid specific) Mitoferrin 2 (ubiquitous)

MFRN-1

SLC25A37 (8p21.2) SLC25A28 (10q24.2) FTMT (5q21.3) SFXN4 (10q25-26) Abcb10 (1q42.13) ABCB6 (2q36) Fxn (9q21.11)

Mitochondrial ferritin Sideroflexin-4 ATP-binding cassette family member B 10 ATP-binding cassette family member B 6 Frataxin

ABC transporter type B7

MFRN-2 MtF SFXN4 ABCB10 ABCB6 FXN

ABCB7

ABCB7 (Xq13.3)

Iron regulatory protein 1

IRP1

ACO1 (9p21.1)

Iron regulatory protein 2

IRP2

IREB2 (15q25.1)

Ferrochelatase

FECH

5-amino-levulinic acid synthase

ALAS2

Fech (18q21.3) Alas2 (Xp11.21)

Mitochondrial iron metabolism Machinery Mitochondrial Iron Delivery Unknown

Unknown

Diamon-Blackfan Anemia

Mitochondrial Iron Delivery

Unknown

Storing Mitochondrial Iron

Higher expression in AD and neuroprotective effect[85] Unknown

Erythropoietic protoporphyria Hypochromic anemia (?), Friedreich's ataxia Anemia sideroblastic, Friedreich ataxia Siderocytic anemia

Unknown

Unknown

Porphyrin Importer

Unknown

Unknown

Mitochondrial Iron Chaperone

Unknown

Friedreich Ataxia

Unknown

X-linked sideroblastic anemia and ataxia, refractory anemia with ring sideroblasts

Mitochondrial transport iron to synthesis heme Erythroid heme biosynthesis

Iron Cellular Regulation Machinery Iron-dependent binding to No change in comparison to control brain iron responsive elements on tissue[103] mRNA Iron-dependent binding to Altered levels in AD brain[103] iron responsive elements on mRNA Insertion of iron into Increased in AD subjects[42] porphyrin Heme biogenesis Unknown

Friedreich ataxia

[14, 6870]

[71] [14, 72, 73] [77, 78] [79, 80]

[81-83] [81, 84] [86-90] [91] [92-94] [95, 96] [89]

[97-102]

[104, 105]

Unknown [105] Erythropoietic protoporphyria β-thalassemia, sicklecell anemia, X linked sideroblastic anemia

[8, 106108] [109111]

3-hydroxy butyrate dehydrogenase-2 Glutaredoxin 5

BDH2 GRX5

ATP-binding cassette family member C, G2

ABCG2

Heme responsive gene 1

Hepcidin

Hemochromatosis protein

Transferrin receptor 2

Hemojuvelin

Mothers against decapentaplegic homolog 4 Neogenin

Unknown

Unknown

Facilitator of ISC biogenesis

Unknown

Sideroblastic anemia, Microcytic anemia with ring sideroblasts

Partial Heme exporter; PPIX exporter

HRG1

HRG1 (12q13.11)

HEPC

HAMP (19q13)

Exporter of heme into cytoplasm from lysosomes Iron Systemic Regulation Machinery Master of Systemic Iron Unknown balance-Release regulator

HFE (6p21.3)

Positive regulator of Hepcidin expression

HFE

TfR2

HJV

Smad4 Neogenin

BMP6

Mammalian target of Rapamycin Transmembrane protease, serine 6 (Matripase-2)

mTOR

Growth differentiation factor

Siderophore Biogenesis

Abcg2 (4q22.1)

Bone morphogenic protein 6

Huntingtin protein

Bdh2 or Dhrs6 (4q24) Grx5 (14q32.13)

TMPRSS6

Huntingtin GDF15

• ROS-mediated toxicity reduction[116] • Up regulated in AD Brain and prevent blood-borne Aβ peptides to enter to brain[117] Unknown

• No relation[122] • C282Y & H63D HFE mutations are protective variants[123, 124] • Not involved in AD[125] • Synergistic effect on AD with Tf [3, 126] Unknown

[118]s Unknown

Hepcidin-related hemochromatosis (Type 2B)- Principle peptide in infection diseases HFE-related hemochromatosis (type1)

Positive regulator of Hepcidin expression

HFE2 (1q21.1)

Positive regulator of Hepcidin expression

Unknown

Smad4 (18q21.1) Neo1 (15q22.3-q23)

Positive regulator of Hepcidin expression For the processing and release of HJV

Unknown

Iron overload

Unknown

BMP6 (6p24-p23) mTOR (1p36.2) TMPRSS6

Upstream regulator of Hepcidin expression Modulating TfR1 stability

Unknown

Unknown (Altered growth patterns of neuronal axons) Iron overload

HTT (4p16.3) GDF15

Negative regulator of Hepcidin expression

[112115]

Unknown

TfR2 (7q22)

Altered expression in lymphocytes of AD individuals[141] Unknown

[19]

TFR2-related hemochromatosis (Type 3) HJV-related hemochromatosis (Type 2A)

Anemia

TfR trafficking

Accumulates in neurons and glia[147]

Iron-refractory iron deficiency anemia (IRIDA), microcytic anemia Unknown

Suppression of Hepcidin

Unknown

Unknown

[105]

[119121]

[127]

[14, 128]

[129132] [133, 134] [135137] [138140] [142, 143] [131, 144-146] [148] [149,

15 Twisted gastrulation protein homolog 1 precursor

TWSG1

(19p13.11) TWSG1 (18p11.3)

during β-thalassemia Negative regulator of hepcidin expression

150] Unknown

Unknown [151]

Table References:

[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]

Landeghem GFV, Sikström C, Beckman LE, Adolfsson R, Beckman L (1998) Transferrin C2, metal binding and Alzheimer's disease. Neuroreport 9, 177-177. Mainous 3rd A, Eschenbach SL, Wells BJ, Everett CJ, Gill JM (2005) Cholesterol, transferrin saturation, and the development of dementia and Alzheimer’s disease: results from an 18-year population-based cohort. Fam Med 37, 36-42. Robson K, Lehmann D, Wimhurst V, Livesey K, Combrinck M, Merryweather-Clarke A, Warden D, Smith A (2004) Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer’s disease. J Med Genet 41, 261-265. Squitti R, Salustri C, Siotto M, Ventriglia M, Vernieri F, Lupoi D, Cassetta E, Rossini PM (2010) Ceruloplasmin/Transferrin ratio changes in Alzheimer's disease. Int J Alzheimer's Dis 2011. Graham R, Chua AG, Trinder D (2012) Plasma Iron and Iron Delivery to the Tissues In Iron Physiology and Pathophysiology in Humans, Anderson GJ, McLaren GD, eds. Humana Press, pp. 117-139. Lim JE, Jin O, Bennett C, Morgan K, Wang F, Trenor CC, Fleming MD, Andrews NC (2005) A mutation in Sec15l1 causes anemia in hemoglobin deficit (hbd) mice. Nat Genet 37, 1270-1273. White RA, Boydston LA, Brookshier TR, McNulty SG, Nsumu NN, Brewer BP, Blackmore K (2005) Iron metabolism mutant hbd mice have a deletion in Sec15l1, which has homology to a yeast gene for vesicle docking. Genomics 86, 668-673. Muckenthaler M, Lill R (2012) Cellular Iron Physiology In Iron Physiology and Pathophysiology in Humans, Anderson GJ, McLaren GD, eds. Humana Press, pp. 27-50. Choe YH, OH YJ, LEE NG, IMOTO I, ADACHI Y, TOYODA N, GABAZZA EC (2003) Lactoferrin sequestration and its contribution to iron‐deficiency anemia in Helicobacter pylori‐ infected gastric mucosa. J Gastroen Hepatol 18, 980-985. Koikawa N, Nagaoka I, Yamaguchi M, Hamano H, Yamauchi K, Sawaki K (2008) Preventive effect of lactoferrin intake on anemia in female long distance runners. Biosci Biotech Bioch 72, 931-935. Kalaria R, Sromek S, Grahovac I, Harik S (1992) Transferrin receptors of rat and human brain and cerebral microvessels and their status in Alzheimer's disease. Brain Res 585, 8793. Morris C, Candy J, Kerwin J, Edwardson J (1994) Transferrin receptors in the normal human hippocampus and in Alzheimer's disease. Neuropathology and applied neurobiology 20, 473-477. Jamieson SE, White JK, Howson JM, Pask R, Smith AN, Brayne C, Evans JG, Xuereb J, Cairns NJ, Rubinsztein DC (2005) Candidate gene association study of solute carrier family 11a members 1 ( SLC11A1) and 2 (SLC11A2) genes in Alzheimer's disease. Neurosci Lett 374, 124-128. Srai S, Sharp P (2012) Proteins of Iron Homeostasis In Iron Physiology and Pathophysiology in Humans, Anderson GJ, McLaren GD, eds. Humana Press, pp. 3-25. Bishop GM, Scheiber IF, Dringen R, Robinson SR (2010) Synergistic accumulation of iron and zinc by cultured astrocytes. J Neural Transm 117, 809-817.

[16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48]

Liuzzi JP, Aydemir F, Nam H, Knutson MD, Cousins RJ (2006) Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. P Natl Acad Sci Usa 103, 13612-13617. Pinilla-Tenas JJ, Sparkman BK, Shawki A, Illing AC, Mitchell CJ, Zhao N, Liuzzi JP, Cousins RJ, Knutson MD, Mackenzie B (2011) Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. Am J Physiol-Cell Ph 301, C862-C871. Jenkitkasemwong S, Wang C-Y, Mackenzie B, Knutson MD (2012) Physiologic implications of metal-ion transport by ZIP14 and ZIP8. Biometals 25, 643-655. Devireddy LR, Hart DO, Goetz DH, Green MR (2010) A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell 141, 1006-1017. Weiss G (2012) Iron and the Reticuloendothelial System In Iron Physiology and Pathophysiology in Humans, Anderson GJ, McLaren GD, eds. Humana Press, pp. 211-231. Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, Sharp JJ, Fujiwara Y, Barker JE, Fleming MD (2005) Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet 37, 1264-1269. Lambe T, Simpson RJ, Dawson S, Bouriez-Jones T, Crockford TL, Lepherd M, Latunde-Dada GO, Robinson H, Raja KB, Campagna DR (2009) Identification of a Steap3 endosomal targeting motif essential for normal iron metabolism. Blood 113, 1805-1808. McKie AT, Barrow D, Latunde-Dada GO, Rolfs A, Sager G, Mudaly E, Mudaly M, Richardson C, Barlow D, Bomford A (2001) An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291, 1755-1759. Frenkel D, Wilkinson K, Zhao L, Hickman SE, Means TK, Puckett L, Farfara D, Kingery ND, Weiner HL, El Khoury J (2013) Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat Commun 4. Li JY, Paragas N, Ned RM, Qiu A, Viltard M, Leete T, Drexler IR, Chen X, Sanna-Cherchi S, Mohammed F (2009) Scara5 is a ferritin receptor mediating non-transferrin iron delivery. Dev Cell 16, 35-46. Chen TT, Li L, Chung D-H, Allen CD, Torti SV, Torti FM, Cyster JG, Chen C-Y, Brodsky FM, Niemi EC (2005) TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. J Exp Med 202, 955-965. Yamamoto S, Wajima T, Hara Y, Nishida M, Mori Y (2007) Transient receptor potential channels in Alzheimer's disease. BBA Mol Basis Dis 1772, 958-967. Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci 31, 454-463. Dong X-P, Cheng X, Mills E, Delling M, Wang F, Kurz T, Xu H (2008) The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455, 992-996. Duffy SP, Shing J, Saraon P, Berger LC, Eiden MV, Wilde A, Tailor CS (2010) The Fowler syndrome-associated protein FLVCR2 is an importer of heme. Mol Cell Biol 30, 5318-5324. Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman H-J, Law SA, Moestrup SK (2001) Identification of the haemoglobin scavenger receptor. Nature 409, 198-201. Schaer DJ, Schaer CA, Buehler PW, Boykins RA, Schoedon G, Alayash AI, Schaffner A (2006) CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin. Blood 107, 373-380. Smith A (2012) Iron Salvage Pathways In Iron Physiology and Pathophysiology in Humans, Anderson GJ, McLaren GD, eds. Humana Press, pp. 141-171. Kang DE, Pietrzik CU, Baum L, Chevallier N, Merriam DE, Kounnas MZ, Wagner SL, Troncoso JC, Kawas CH, Katzman R (2000) Modulation of amyloid β-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor–related protein pathway. Jcl 106, 1159-1166. Sanchez L, Alvarez V, Gonzalez P, Gonzalez I, Alvarez R, Coto E (2001) Variation in the LRP‐associated protein gene (LRPAP1) is associated with late‐onset Alzheimer disease. Am J Med Genet 105, 76-78. Shayeghi M, Latunde-Dada GO, Oakhill JS, Laftah AH, Takeuchi K, Halliday N, Khan Y, Warley A, McCann FE, Hider RC (2005) Identification of an intestinal heme transporter. Cell 122, 789-801. Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C, Zhao R, Akabas MH, Goldman ID (2006) Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127, 917-928. Simpson IA, Chundu KR, Davies‐Hill T, Honer WG, Davies P (1994) Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer's disease. Ann Neurol 35, 546-551. Mooradian A, Chung H, Shah G (1997) GLUT-1 expression in the cerebra of patients with Alzheimer’s disease. Neurobiol Aging 18, 469-474. Hartz AM, Miller DS, Bauer B (2010) Restoring blood-brain barrier P-glycoprotein reduces brain amyloid-β in a mouse model of Alzheimer's disease. Mol Pharmacol 77, 715-723. Lane DJ, Lawen A (2009) Ascorbate and plasma membrane electron transport—Enzymes vs efflux. Free Radical Bio Med 47, 485-495. Atamna H, Frey W A role for heme in Alzheimer’s disease: Heme binds amyloid beta and has altered metabolism. Proc Natl Acad Sci USA 101, 1. Smith A, Kadish K, Smith K, Guilard R, Hacksack N (2011) Mechanisms of cytoprotection by hemopexin. Handbook of Porphyrin Science with Applications to Chemistry, Physics, Materials Science, Engineering, Biology and Medicine 15, 217-355. den Velde WO, Stam F (1973) Haptoglobin types and subtypes in Alzheimer's disease and senile dementia. Humangenetik 20, 25-30. Zhang R, Barker L, Pinchev D, Marshall J, Rasamoelisolo M, Smith C, Kupchak P, Kireeva I, Ingratta L, Jackowski G (2004) Mining biomarkers in human sera using proteomic tools. Proteomics 4, 244-256. Abraham J-D, Calvayrac-Pawlowski S, Cobo S, Salvetat N, Vicat G, Molina L, Touchon J, Michel B-F, Molina F, Verdier J-M (2011) Combined measurement of PEDF, haptoglobin and tau in cerebrospinal fluid improves the diagnostic discrimination between alzheimer's disease and other dementias. Biomarkers 16, 161-171. Dhaliwal G, Cornett PA, Tierney Jr LM (2004) Hemolytic anemia. Am Fam Physician 69, 2599-2606. Nielsen MJ, Moestrup SK (2009) Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging. Blood 114, 764-771.

[49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80]

Schipper HM (2007) Biomarker potential of heme oxygenase-1 in Alzheimer’s disease and mild cognitive impairment. Biomarkers 1, 375-385. Schipper HM (2011) Heme oxygenase-1 in Alzheimer disease: a tribute to Moussa Youdim. J Neural Transm 118, 381-387. Shibata N, Ohnuma T, Baba H, Arai H (2009) No genetic association between polymorphisms of heme oxygenase 1 and 2 and Alzheimer’s disease in a Japanese population. Dement Geriatr Cogn 27, 273-277. West AR, Oates PS (2008) Mechanisms of heme iron absorption: current questions and controversies. World journal of gastroenterology: WJG 14, 4101. Abraham NG, Kappas A (2008) Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60, 79-127. Doré S (2002) Decreased activity of the antioxidant heme oxygenase enzyme: implications in ischemia and in Alzheimer’s disease. Free Radical Bio Med 32, 1276-1282. Connor JR, Snyder BS, Arosio P, Loeffler DA, LeWitt P (1995) A quantitative analysis of isoferritins in select regions of aged, parkinsonian, and Alzheimer's diseased brains. J Neurochem 65, 717-724. Arosio P, Ingrassia R, Cavadini P (2009) Ferritins: a family of molecules for iron storage, antioxidation and more. BBA Gen Subjects 1790, 589-599. Theil E (2012) Concentrating, Storing, and Detoxifying Iron: The Ferritins and Hemosiderin In Iron Physiology and Pathophysiology in Humans, Anderson GJ, McLaren GD, eds. Humana Press, pp. 63-78. Vidal R, Ghetti B, Takao M, Brefel-Courbon C, Uro-Coste E, Glazier B, Siani V, Benson M, Calvas P, Miravalle L (2004) Intracellular ferritin accumulation in neural and extraneural tissue characterizes a neurodegenerative disease associated with a mutation in the ferritin light polypeptide gene. J Neuropath Exp Neur 63, 363-380. Hetet G, Devaux I, Soufir N, Grandchamp B, Beaumont C (2003) Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations. Blood 102, 1904-1910. Levi S, Cozzi A, Arosio P (2005) Neuroferritinopathy: a neurodegenerative disorder associated with L-ferritin mutation. Best Pract Res Cl Ha 18, 265-276. Shi H, Bencze KZ, Stemmler TL, Philpott CC (2008) A cytosolic iron chaperone that delivers iron to ferritin. Science 320, 1207-1210. Abboud S, Haile DJ (2000) A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 275, 19906-19912. De Domenico I, Ward DM, Nemeth E, Vaughn MB, Musci G, Ganz T, Kaplan J (2005) The molecular basis of ferroportin-linked hemochromatosis. P Natl Acad Sci Usa 102, 89558960. Castellani RJ, Smith MA, Nunomura A, Harris PL, Perry G (1999) Is increased redox-active iron in Alzheimer disease a failure of the copper-binding protein ceruloplasmin? Free Radical Bio Med 26, 1508-1512. Loeffler D, DeMaggio A, Juneau P, Brickman C, Mashour G, Finkelman J, Pomara N, LeWitt P (1994) Ceruoplasmin Is Increased in Cerebrospinal Fluid in Alzheimer's Disease but Not Parkinson's Disease. Alz Dis Assoc Dis 8, 190-197. Capo CR, Arciello M, Squitti R, Cassetta E, Rossini PM, Calabrese L, Rossi L (2008) Features of ceruloplasmin in the cerebrospinal fluid of Alzheimer’s disease patients. Biometals 21, 367-372. Squitti R, Quattrocchi CC, Salustri C, Rossini PM (2008) Ceruloplasmin fragmentation is implicated in'free'copper deregulation of Alzheimer disease. Prion 2, 23-27. Yoshida K, Furihata K, Takeda Si, Nakamura A, Yamamoto K, Morita H, Hiyamuta S, Ikeda S-i, Shimizu N, Yanagisawa N (1995) A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat Genet 9, 267-272. Jeong SY, David S (2003) Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem 278, 27144-27148. Cherukuri S, Potla R, Sarkar J, Nurko S, Harris ZL, Fox PL (2005) Unexpected role of ceruloplasmin in intestinal iron absorption. Cell Metab 2, 309-319. Wang F, Paradkar PN, Custodio AO, Ward DM, Fleming MD, Campagna D, Roberts KA, Boyartchuk V, Dietrich WF, Kaplan J (2007) Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice. Nat Genet 39, 1025-1032. Vulpe CD, Kuo Y-M, Murphy TL, Cowley L, Askwith C, Libina N, Gitschier J, Anderson GJ (1999) Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 21, 195-199. Beutler E, Felitti V, Gelbart T, Ho N (2001) Genetics of iron storage and hemochromatosis. Drag Metab Dispos 29, 495-499. Rogers JT, Randall JD, Cahill CM, Eder PS, Huang X, Gunshin H, Leiter L, McPhee J, Sarang SS, Utsuki T (2002) An iron-responsive element type II in the 5′-untranslated region of the Alzheimer's amyloid precursor protein transcript. J Biol Chem 277, 45518-45528. Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek D (1987) Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science 235, 877-880. Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2, a006270. Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA (2010) Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142, 857-867. Bekris L, Galloway N, Millard S, Lockhart D, Li G, Galasko D, Farlow M, Clark C, Quinn J, Kaye J (2011) Amyloid precursor protein (APP) processing genes and cerebrospinal fluid APP cleavage product levels in Alzheimer's disease. Neurobiol Aging 32, 556. e513-556. e523. Keel SB, Doty RT, Yang Z, Quigley JG, Chen J, Knoblaugh S, Kingsley PD, De Domenico I, Vaughn MB, Kaplan J (2008) A heme export protein is required for red blood cell differentiation and iron homeostasis. Science 319, 825-828. Rey MA, Duffy SP, Brown JK, Kennedy JA, Dick JE, Dror Y, Tailor CS (2008) Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis. Haematologica 93, 1617-1626.

[81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109]

Shaw GC, Cope JJ, Li L, Corson K, Hersey C, Ackermann GE, Gwynn B, Lambert AJ, Wingert RA, Traver D (2006) Mitoferrin is essential for erythroid iron assimilation. Nature 440, 96-100. Troadec M-B, Warner D, Wallace J, Thomas K, Spangrude GJ, Phillips J, Khalimonchuk O, Paw BH, Ward DM, Kaplan J (2011) Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria. Blood 117, 5494-5502. Wang Y, Langer NB, Shaw GC, Yang G, Li L, Kaplan J, Paw BH, Bloomer JR (2011) Abnormal mitoferrin-1expression in patients with erythropoietic protoporphyria. Exp Hematol 39, 784-794. Richardson DR, Lane DJ, Becker EM, Huang ML-H, Whitnall M, Rahmanto YS, Sheftel AD, Ponka P (2010) Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol. P Natl Acad Sci Usa 107, 10775-10782. Wang L, Yang H, Zhao S, Sato H, Konishi Y, Beach TG, Abdelalim EM, Bisem NJ, Tooyama I (2011) Expression and localization of mitochondrial ferritin mRNA in Alzheimer's disease cerebral cortex. PLoS One 6, e22325. Levi S, Corsi B, Bosisio M, Invernizzi R, Volz A, Sanford D, Arosio P, Drysdale J (2001) A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem 276, 2443724440. Cazzola M, Invernizzi R, Bergamaschi G, Levi S, Corsi B, Travaglino E, Rolandi V, Biasiotto G, Drysdale J, Arosio P (2003) Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia. Blood 101, 1996-2000. Nie G, Sheftel AD, Kim SF, Ponka P (2005) Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis. Blood 105, 2161-2167. Napier I, Ponka P, Richardson DR (2005) Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood 105, 1867-1874. Campanella A, Rovelli E, Santambrogio P, Cozzi A, Taroni F, Levi S (2009) Mitochondrial ferritin limits oxidative damage regulating mitochondrial iron availability: hypothesis for a protective role in Friedreich ataxia. Hum Mol Genet 18, 1-11. Zheng H, Ji C, Zou X, Wu M, Jin Z, Yin G, Li J, Feng C, Cheng H, Gu S (2003) Molecular cloning and characterization of a novel human putative transmembrane protein homologous to mouse sideroflexin associated with sideroblastic anemia. Mitochondr DNA 14, 369-373. Shirihai OS, Gregory T, Yu C, Orkin SH, Weiss MJ (2000) ABC-me: a novel mitochondrial transporter induced by GATA-1 during erythroid differentiation. The EMBO journal 19, 2492-2502. Chen W, Paradkar PN, Li L, Pierce EL, Langer NB, Takahashi-Makise N, Hyde BB, Shirihai OS, Ward DM, Kaplan J (2009) Abcb10 physically interacts with mitoferrin-1 (Slc25a37) to enhance its stability and function in the erythroid mitochondria. P Natl Acad Sci Usa 106, 16263-16268. Chen W, Dailey HA, Paw BH (2010) Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis. Blood 116, 628-630. Krishnamurthy PC, Du G, Fukuda Y, Sun D, Sampath J, Mercer KE, Wang J, Sosa-Pineda B, Murti KG, Schuetz JD (2006) Identification of a mammalian mitochondrial porphyrin transporter. Nature 443, 586-589. Paterson JK, Shukla S, Black CM, Tachiwada T, Garfield S, Wincovitch S, Ernst DN, Agadir A, Li X, Ambudkar SV (2007) Human ABCB6 localizes to both the outer mitochondrial membrane and the plasma membrane. Biochemistry 46, 9443-9452. Bekri S, Kispal G, Lange H, Fitzsimons E, Tolmie J, Lill R, Bishop DF (2000) Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation. Blood 96, 3256-3264. Csere P, Lill R, Kispal G (1998) Identification of a human mitochondrial ABC transporter, the functional orthologue of yeast Atm1p. Febs Lett 441, 266. Pondarré C, Antiochos BB, Campagna DR, Clarke SL, Greer EL, Deck KM, McDonald A, Han A-P, Medlock A, Kutok JL (2006) The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron–sulfur cluster biogenesis. Hum Mol Genet 15, 953-964. Pondarre C, Campagna DR, Antiochos B, Sikorski L, Mulhern H, Fleming MD (2007) Abcb7, the gene responsible for X-linked sideroblastic anemia with ataxia, is essential for hematopoiesis. Blood 109, 3567-3569. Boultwood J, Pellagatti A, Nikpour M, Pushkaran B, Fidler C, Cattan H, Littlewood TJ, Malcovati L, Della Porta MG, Jädersten M (2008) The role of the iron transporter ABCB7 in refractory anemia with ring sideroblasts. PLoS One 3, e1970. Barton J, Lee P, Edwards C (2012) Genetic Testing for Disorders of Iron Homeostasis In Iron Physiology and Pathophysiology in Humans, Anderson GJ, McLaren GD, eds. Humana Press, pp. 529-565. Smith MA, Wehr K, Harris PL, Siedlak SL, Connor JR, Perry G (1998) Abnormal localization of iron regulatory protein in Alzheimer's disease. Brain Res 788, 232-236. Lobmayr L, Brooks DG, Wilson RB (2005) Increased IRP1 activity in Friedreich ataxia. Gene 354, 157-161. Hentze MW, Muckenthaler MU, Galy B, Camaschella C (2010) Two to tango: regulation of Mammalian iron metabolism. Cell 142, 24-38. Scott A, Ansford A, Webster B, Stringer H (1973) Erythropoietic protoporphyria with features of a sideroblastic anaemia terminating in liver failure. Am J Med 54, 251-259. Rademakers L, Koningsberger J, Sorber C, Faille H, Hattum J, Marx J (1993) Accumulation of iron in erythroblasts of patients with erythropoietic protoporphyria. Eur J Clin Invest 23, 130-138. Rüfenacht UB, Gregor A, Gouya L, Tarczynska-Nosal S, Schneider-Yin X, Deybach J-C (2001) New missense mutation in the human ferrochelatase gene in a family with erythropoietic protoporphyria: functional studies and correlation of genotype and phenotype. Clin Chem 47, 1112-1113. Cotter PD, May A, Li L, Al-Sabah A, Fitzsimons EJ, Cazzola M, Bishop DF (1999) Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing Xlinked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis. Blood 93, 1757-1769.

[110] [111] [112] [113] [114] [115] [116] [117] [118] [119] [120] [121] [122] [123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139]

Cazzola M, May A, Bergamaschi G, Cerani P, Ferrillo S, Bishop DF (2002) Absent phenotypic expression of X-linked sideroblastic anemia in one of 2 brothers with a novel ALAS2 mutation. Blood 100, 4236-4238. Ajioka RS, Phillips JD, Kushner JP (2006) Biosynthesis of heme in mammals. BBA Mol Cell Res 1763, 723-736. Bellı́ G, Polaina J, Tamarit J, de la Torre MaA, Rodrı́guez-Manzaneque MaT, Ros J, Herrero E (2002) Structure-function analysis of yeast Grx5 monothiol glutaredoxin defines essential amino acids for the function of the protein. J Biol Chem 277, 37590-37596. Rodrı́guez-Manzaneque MaT, Tamarit J, Bellı́ G, Ros J, Herrero E (2002) Grx5 is a mitochondrial glutaredoxin required for the activity of iron/sulfur enzymes. Mol Biol Cell 13, 1109-1121. Camaschella C, Campanella A, De Falco L, Boschetto L, Merlini R, Silvestri L, Levi S, Iolascon A (2007) The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload. Blood 110, 1353-1358. Ye H, Jeong SY, Ghosh MC, Kovtunovych G, Silvestri L, Ortillo D, Uchida N, Tisdale J, Camaschella C, Rouault TA (2010) Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. J Clin Invest 120, 1749. Shen S, Callaghan D, Juzwik C, Xiong H, Huang P, Zhang W (2010) ABCG2 reduces ROS‐mediated toxicity and inflammation: a potential role in Alzheimer’s disease. J Neurochem 114, 1590-1604. Xiong H, Callaghan D, Jones A, Bai J, Rasquinha I, Smith C, Pei K, Walker D, Lue L-F, Stanimirovic D (2009) ABCG2 Is Upregulated in Alzheimer's Brain with Cerebral Amyloid Angiopathy and May Act as a Gatekeeper at the Blood–Brain Barrier for Aβ1–40 Peptides. J Neurosci 29, 5463-5475. Krishnamurthy P, Ross DD, Nakanishi T, Bailey-Dell K, Zhou S, Mercer KE, Sarkadi B, Sorrentino BP, Schuetz JD (2004) The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem 279, 24218-24225. Park CH, Valore EV, Waring AJ, Ganz T (2001) Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 276, 7806-7810. Drakesmith H, Prentice AM (2012) Hepcidin and the iron-infection axis. Science 338, 768-772. Ganz T, Nemeth E (2011) Hepcidin and disorders of iron metabolism. Annu Rev Med 62, 347-360. Alizadeh B, Njajou O, Millan M, Hofman A, Breteler M, Duijn Cv (2009) HFE variants, APOE and Alzheimer's disease: findings from the population-based Rotterdam study. Neurobiol Aging 30, 330-332. Correia AP, Pinto JP, Dias V, Mascarenhas C, Almeida S, Porto G (2009) CAT53 and HFE alleles in Alzheimer's disease: A putative protective role of the C282Y HFE mutation. Neurosci Lett 457, 129-132. Blázquez L, De Juan D, Ruiz-Martinez J, Emparanza J, Saenz A, Otaegui D, Sistiaga A, Martinez-Lage P, Lamet I, Samaranch L (2007) Genes related to iron metabolism and susceptibility to Alzheimer's disease in Basque population. Neurobiol Aging 28, 1941. Guerreiro RJ, Bras JM, Santana I, Januario C, Santiago B, Morgadinho AS, Ribeiro MH, Hardy J, Singleton A, Oliveira C (2006) Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort. BMC neurology 6, 24. Kauwe J, Bertelsen S, Mayo K, Cruchaga C, Abraham R, Hollingworth P, Harold D, Owen M, Williams J, Lovestone S (2010) Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimer's disease. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 153, 955-959. Camaschella C, Poggiali E (2011) Inherited disorders of iron metabolism. Curr Opin Pediatr 23, 14-20. Camaschella C, Roetto A, Calì A, De Gobbi M, Garozzo G, Carella M, Majorano N, Totaro A, Gasparini P (2000) The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 25, 14-15. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dubé M-P, Andres L, MacFarlane J, Sakellaropoulos N, Politou M (2003) Mutations in HFE2 cause iron overload in chromosome 1q–linked juvenile hemochromatosis. Nat Genet 36, 77-82. Niederkofler V, Salie R, Arber S (2005) Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. Jcl 115, 2180-2186. Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C (2008) The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab 8, 502-511. Chen W, Huang FW, de Renshaw TB, Andrews NC (2011) Skeletal muscle hemojuvelin is dispensable for systemic iron homeostasis. Blood 117, 6319-6325. Wang R-H, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, Cooperman S, Eckhaus M, Rouault T, Mishra L (2005) A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2, 399-409. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY (2007) Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. Jcl 117, 1933-1939. Zhang A-S, West AP, Wyman AE, Bjorkman PJ, Enns CA (2005) Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells. J Biol Chem 280, 33885-33894. Zhang A-S, Yang F, Meyer K, Hernandez C, Chapman-Arvedson T, Bjorkman PJ, Enns CA (2008) Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane. J Biol Chem 283, 17494-17502. Lee J, Prohaska JR, Thiele DJ (2001) Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development. P Natl Acad Sci Usa 98, 6842-6847. Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth M-P (2009) Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 41, 478481. Andriopoulos Jr B, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin HY (2009) BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 41, 482-487.

[140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151]

Camaschella C (2009) BMP6 orchestrates iron metabolism. Nat Genet 41, 386-388. Paccalin M, Pain-Barc S, Pluchon C, Paul C, Besson M-N, Carret-Rebillat A-S, Rioux-Bilan A, Gil R, Hugon J (2006) Activated mTOR and PKR kinases in lymphocytes correlate with memory and cognitive decline in Alzheimer’s disease. Dement Geriatr Cogn 22, 320-326. Sofroniadou S, Kassimatis T, Goldsmith D (2010) Anaemia, microcytosis and sirolimus—is iron the missing link? Nephrol Dial Transpl 25, 1667-1675. Bayeva M, Khechaduri A, Puig S, Chang H-C, Patial S, Blackshear PJ, Ardehali H (2012) mTOR regulates cellular iron homeostasis through Tristetraprolin. Cell Metab 16, 645-657. Finberg KE, Heeney MM, Campagna DR (2008) Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 40, 569-571. Du X, She E, Gelbart T, Truksa J, Lee P, Xia Y, Khovananth K, Mudd S, Mann N, Moresco EMY (2008) The serine protease TMPRSS6 is required to sense iron deficiency. Sci Signal 320, 1088. Finberg KE, Whittlesey RL, Fleming MD, Andrews NC (2010) Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood 115, 3817-3826. Singhrao S, Thomas P, Wood J, MacMillan J, Neal J, Harper P, Jones A (1998) Huntingtin protein colocalizes with lesions of neurodegenerative diseases: An investigation in Huntington's, Alzheimer's, and Pick's diseases. Exp Neurol 150, 213-222. Jones A, Wood J, Harper P (1997) Huntington disease: advances in molecular and cell biology. J Inherit Metab Dis 20, 125-138. Tanno T, Bhanu NV, Oneal PA, Goh S-H, Staker P, Lee YT, Moroney JW, Reed CH, Luban NL, Wang R-H (2007) High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 13, 1096-1101. Finkenstedt A, Bianchi P, Theurl I, Vogel W, Witcher DR, Wroblewski VJ, Murphy AT, Zanella A, Zoller H (2009) Regulation of iron metabolism through GDF15 and hepcidin in pyruvate kinase deficiency. Brit J Haematol 144, 789-793. Tanno T, Porayette P, Sripichai O, Noh S-J, Byrnes C, Bhupatiraju A, Lee YT, Goodnough JB, Harandi O, Ganz T (2009) Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood 114, 181-186.

Supplementary Table 2. Homeostatic Machinery Of Copper Metabolism With A Link To Alzheimer’s Disease And Other Associated Disorders

Protein

Protein abbreviation

Gene (Human Chromosomal location)

Function in Iron Metabolism

Link with Alzheimer's Disease

Human Disorders of copper Metabolism

Ref

Copper Transport and Uptake

pper Transporter-1

CTR1

pper Transporter-2

CTR2

Divalent metal-ion transporter-1 Albumin

DMT1

α2-macroglobulin

A2M

Alb

Factor V

F5

Factor VIII

F8

SLC31A1 (9q32) SLC31A2 (9q32) SLC11A2 (12q13) Alb (4q13.3) A2M (12p13.31)

Cuprous copper importer

Unknown

Unknown

[1, 2]

Vesicular copper transporter, cellular membrane uptake Cuprous copper importer (Intestinal and BBB) Intestine to liver copper carrier

Unknown

Unknown

[3]

No major effect[4]

Unknown

[5]

Serum Albumin is reduced in AD patients[6, 7]

Unknown

[8]

Intestine to liver copper carrier

Unknown

[11]

F5 (1q23) F8 (Xq28)

Blood clotting; Unknown role in copper metabolisms Blood clotting; Unknown role in copper metabolisms

• A2M is not associated with AD in Han Chinese population[9] • Involved in Aβ clearance[10] Unknown

Unknown

[12]

Unknown

Unknown

[12, 13]

Prion protein

PRNP

Hephaestin

HEPH

PRNP (20p13)

Copper reductase facilitating copper uptake, antioxidant function in synaptic clefts, modulating NMDAR activity mediated by copper[14]

• Prevents β-amyloid production[15] • PrPC is necessary for the inhibition of LTP mediated by β-amyloid oligomers[16] • PrPC mediates impairment of synaptic plasticity by amyloid-beta oligomers[17] (Kessels et al. [18]and Balducci et al. [19] challenged the two above study, highlighting the negative effect of β-amyloid oligomers independency on PrPc ) • PrPc is required for β-amyloid oligomersinduced neuronal death[20] • Promotes β-amyloid fibrillization in bigenicmice (TgCRND8/Tg7)[21] • PrPC is reduced in AD[22] • Polymorphisms implicated in AD[23, 24] (Poleggi et al. [25]didn’t not support the role of PRNP polymorphism in AD)

Unknown

[26]

[27]

HEPH (Xq11-q12) CP (3q23-q25)

Gut and CNS ferroxidase

Unknown

Unknown

Secreted Ferrous Oxidase

• • • • •

Hereditary aceruloplasminemia

Ceroluplasmin

CP

Presenilin1, 2

PSEN1, 2

PSEN1 (14q24.3) PSEN2 (1q31-q42)

Promote Dietary Copper Uptake, Maintain Copper Chaperone of SOD1 activity

myloid β precursor protein

APP

APP (21q21.3)

Brain copper transport, CNS ferroxidase

Precursor of β-amyloid[43] (Amyloidogenic pathways[44]), reduces copper[45]

Unknown

[46-49]

ATX1 antioxidant protein 1

ATOX1

ATOX1 (5q32)

Unknown

Wilson and Menkes Disease

[27, 50]

ATPase, Cu++ ransporting, Alpha

ATP7A

ATP7A (Xq21.1)

Copper chaperone for coppertransporting ATPases, storage of labile copper Copper Transport into TGN and out of cells

Unknown

[51-53]

ATPase, Cu++ ransporting, Beta pper chaperone for peroxide dismutase

ATP7B

ATP7B (13q14.3) CCS (11q13)

Copper transport into TGN; copper excretion in bile Cytoplasmic Copper chaperone for SOD1

Unknown

Menkes Disease, Occipital horn syndrome (OHS) Wilson Disease, Menkes Disease Unknown

Increased in AD CSF[28] Decreased activity in AD CSF[29] cp fragmentation in AD serum[30] Defective CP observed[31] Mutation in the PSEN1 is associated with EOAD[33-37] • Mutation in the PSEN2 is associated with rare EOAD[38-40]

[27, 32]

[41, 42]

Copper Cellular Regulatory Machinery

CCS

CCS deficiency increases β-amyloid production[57] and oligomerization[58]

[54-56] [27, 59]

tochrome c oxidase assembly 11 tochrome c oxidase assembly 17

COX11

-linked inhibitor of apoptosis FK506-binding protein 52

XIAP

pecificity protein 1

SP1

COX17

FKBP52

Cox11 (17q22) Cox17 (3q13.33) XIAP (Xq25) FKBP52 (6p21.31) SP1 (12q13.1)

Mitochondrial copper chaperone Delivers Copper to intermembrane space of Mitochondria Ubiquitination of COMMD1 and CCS, Hepatic efflux In neurons it interacts with Atox1

Unknown

Unknown

[60]

Unknown

Unknown

[61-63]

Elevated Levels of XIAP in AD cases[64]

Wilson’s Disease

[65, 66]

Highly expressed in AD brain and modulates toxicity of Aβ peptides[67]

Unknown

[68]

Regulates expression of hCtr1 under copper-stressed conditions

• Dysregulation of Sp1 transcription factor in AD[69, 70] • Regulates Human FE65[71]

Unknown

[72]

Copper Storage Machinery

Metallothionein1-4

MT1-4

MTs (16q13)

Cytoplasmic Copper (Zinc & Cadmium) storage protein, MT3 is involved in brain Cu and Zn homeostasis

Zn7MT-3 protects neurons from toxic Aβ1-40 peptide by removing Cu from Aβ:Cu oligomers[73]

Menkes and Wilson’s diseases

[74-76]

Mitochondrial Copper metabolism Machinery

tochrome c oxidase assembly protein1 tochrome c oxidase assembly protein2

opper metabolism (Murr1) domain containing 1

SCO1 SCO2

COMMD1

SCO1 (17p13.1) SCO2 (22q13.33)

Mitochondrial copper Unknown chaperone Mitochondrial copper Unknown chaperone Copper Export Machinery

Unknown

[77]

Unknown

[77]

COMMD1 (2p15)

Interactome of ATP7B for biliary copper excretion

Wilson’s Disease

Unknown

[78, 79]

Table References:

[1] [2] [3] [4] [5] [6]

Pope C, Flores A, Kaplan J, Unger V (2011) Structure and function of copper uptake transporters. Curr Top Membr 69, 97-112. Nose Y, Wood LK, Kim B-E, Prohaska JR, Fry RS, Spears JW, Thiele DJ (2010) Ctr1 is an apical copper transporter in mammalian intestinal epithelial cells in vivo that is controlled at the level of protein stability. J Biol Chem 285, 32385-32392. Bertinato J, Swist E, Plouffe L, Brooks S, L'Abbe M (2008) Ctr2 is partially localized to the plasma membrane and stimulates copper uptake in COS-7 cells. Biochem J 409, 731-740. Jamieson SE, White JK, Howson JM, Pask R, Smith AN, Brayne C, Evans JG, Xuereb J, Cairns NJ, Rubinsztein DC (2005) Candidate gene association study of solute carrier family 11a members 1 ( SLC11A1) and 2 (SLC11A2) genes in Alzheimer's disease. Neurosci Lett 374, 124-128. Arredondo M, Muñoz P, Mura CV, Núñez MT (2003) DMT1, a physiologically relevant apical Cu1+ transporter of intestinal cells. Am J Physiol-Cell Ph 284, C1525-C1530. Kim TS, Pae CU, Yoon SJ, Jang WY, Lee NJ, Kim JJ, Lee SJ, Lee C, Paik IH, Lee CU (2006) Decreased plasma antioxidants in patients with Alzheimer's disease. Int J Geriatr Psych 21, 344-348.

[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38]

Squitti R, Ventriglia M, Barbati G, Cassetta E, Ferreri F, Dal Forno G, Ramires S, Zappasodi F, Rossini P (2007) ‘Free’copper in serum of Alzheimer’s disease patients correlates with markers of liver function. J Neural Transm 114, 1589-1594. Linder MC, Goode CA (1991) Biochemistry of copper, Plenum Press. Bian L, Yang JD, Guo TW, Duan Y, Qin W, Sun Y, Feng GY, He L (2005) Association Study of the A2M and LRP1Genes with Alzheimer Disease in the Han Chinese. Biol Psychiat 58, 731-737. Tanzi RE, Bertram L (2005) Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 120, 545-555. Liu N, Lo LS-l, Askary SH, Jones L, Kidane TZ, Nguyen TTM, Goforth J, Chu Y-H, Vivas E, Tsai M (2007) Transcuprein is a macroglobulin regulated by copper and iron availability. J Nutr Biochem 18, 597-608. Linder MC, Hazegh-Azam M (1996) Copper biochemistry and molecular biology. Am J Clin Nutr 63, 797S-811S. Bihoreau N, Pin S, KERSABIEC AM, Vidot F, FONTAINE‐AUPART MP (1994) Copper‐atom identification in the active and inactive forms of plasma‐derived FVIII and recombinant FVIII‐ΔII. Euro J Biochem 222, 41-48. You H, Tsutsui S, Hameed S, Kannanayakal TJ, Chen L, Xia P, Engbers JD, Lipton SA, Stys PK, Zamponi GW (2012) Aβ neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-D-aspartate receptors. P Natl Acad Sci Usa 109, 1737-1742. Kellett KA, Hooper NM (2009) Prion protein and Alzheimer disease. Prion 3, 190-194. Barry AE, Klyubin I, Mc Donald JM, Mably AJ, Farrell MA, Scott M, Walsh DM, Rowan MJ (2011) Alzheimer's disease brain-derived amyloid-β-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J Neurosci 31, 7259-7263. Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-&bgr; oligomers. Nature 457, 1128-1132. Kessels HW, Nguyen LN, Nabavi S, Malinow R (2010) The prion protein as a receptor for amyloid-beta. Nature 466, E3-E4. Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T (2010) Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein. P Natl Acad Sci Usa 107, 2295-2300. Kudo W, Lee H-P, Zou W-Q, Wang X, Perry G, Zhu X, Smith MA, Petersen RB, Lee H-g (2012) Cellular prion protein is essential for oligomeric amyloid-β-induced neuronal cell death. Hum Mol Genet 21, 1138-1144. Schwarze-Eicker K, Keyvani K, Görtz N, Westaway D, Sachser N, Paulus W (2005) Prion protein (PrPc) promotes β-amyloid plaque formation. Neurobiol Aging 26, 1177-1182. Whitehouse IJ, Jackson C, Turner AJ, Hooper NM (2010) Prion protein is reduced in aging and in sporadic but not in familial Alzheimer's disease. J Alzheimers Dis 22, 1023-1031. Golanska E, Hulas-Bigoszewska K, Sieruta M, Zawlik I, Witusik M, Gresner SM, Sobow T, Styczynska M, Peplonska B, Barcikowska M (2009) Earlier onset of Alzheimer's disease: risk polymorphisms within PRNP, PRND, CYP46, and APOE genes. J Alzheimers Dis 17, 359-368. Giannattasio C, Poleggi A, Puopolo M, Pocchiari M, Antuono P, Dal Forno G, Wekstein DR, Matera MG, Seripa D, Acciarri A (2008) Survival in Alzheimer’s Disease Is Shorter in Women Carrying Heterozygosity at Codon 129 of the PRNP Gene and No APOE ε4 Allele. Dement Geriatr Cogn 25, 354-358. Poleggi A, Bizzarro A, Acciarri A, Antuono P, Bagnoli S, Cellini E, Forno GD, Giannattasio C, Lauria A, Matera M (2008) Codon 129 polymorphism of prion protein gene in sporadic Alzheimer’s disease. Euro J Neurol 15, 173-178. Millhauser GL (2007) Copper and the prion protein: methods, structures, function, and disease. Annu Rev Phys Chem 58, 299-320. Kim B-E, Nevitt T, Thiele DJ (2008) Mechanisms for copper acquisition, distribution and regulation. Nat Chem Biol 4, 176-185. Loeffler D, DeMaggio A, Juneau P, Brickman C, Mashour G, Finkelman J, Pomara N, LeWitt P (1994) Ceruoplasmin Is Increased in Cerebrospinal Fluid in Alzheimer's Disease but Not Parkinson's Disease. Alz Dis Assoc Dis 8, 190-197. Capo CR, Arciello M, Squitti R, Cassetta E, Rossini PM, Calabrese L, Rossi L (2008) Features of ceruloplasmin in the cerebrospinal fluid of Alzheimer’s disease patients. Biometals 21, 367-372. Squitti R, Quattrocchi CC, Salustri C, Rossini PM (2008) Ceruloplasmin fragmentation is implicated in'free'copper deregulation of Alzheimer disease. Prion 2, 23-27. Brewer GJ, Kanzer SH, Zimmerman EA, Celmins DF, Heckman SM, Dick R (2010) Copper and ceruloplasmin abnormalities in Alzheimer’s disease. American J Of Alzheimer's Dis & Other Dementias 25, 490-497. Puig S, Thiele DJ (2002) Molecular mechanisms of copper uptake and distribution. Curr Opin Chem Biol 6, 171-180. Guo J, Wei J, Liao S, Wang L, Jiang H, Tang B (2010) A novel presenilin 1mutation (Ser169del) in a Chinese family with early-onset Alzheimer's disease. Neurosci Lett 468, 34-37. Lladó A, Sánchez-Valle R, Rey M, Mercadal P, Almenar C, López-Villegas D, Fortea J, Molinuevo J (2010) New mutation in the PSEN1(E120G) gene associated with early onset Alzheimer's disease. Neurología (English Edition) 25, 13-16. Larner A (2011) Presenilin-1 mutation Alzheimer's disease: A genetic epilepsy syndrome? Epilepsy Behav 21, 20-22. Müller M, Cárdenas C, Mei L, Cheung K-H, Foskett JK (2011) Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling. P Natl Acad Sci Usa 108, 13293-13298. Acosta-Baena N, Sepulveda-Falla D, Lopera-Gómez CM, Jaramillo-Elorza MC, Moreno S, Aguirre-Acevedo DC, Saldarriaga A, Lopera F (2011) Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. Lancet Neurol 10, 213-220. Jayadev S, Leverenz JB, Steinbart E, Stahl J, Klunk W, Yu C-E, Bird TD (2010) Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2. Brain 133, 1143-1154.

[39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71]

Yu C-E, Marchani E, Nikisch G, Muller U, Nolte D, Hertel A, Wijsman EM, Bird TD (2010) The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease. Arch Neurol-Chicago 67, 631-633. Piscopo P, Talarico G, Crestini A, Gasparini M, Malvezzi-Campeggi L, Piacentini E, Lenzi GL, Bruno G, Confaloni A (2010) A novel mutation in the predicted TMIII domain of the PSEN2 gene in an Italian pedigree with atypical Alzheimer's disease. J Alzheimers Dis 20, 43-47. Greenough MA, Volitakis I, Li Q-X, Laughton K, Evin G, Ho M, Dalziel AH, Camakaris J, Bush AI (2011) Presenilins promote the cellular uptake of copper and zinc and maintain copper chaperone of SOD1-dependent copper/zinc superoxide dismutase activity. J Biol Chem 286, 9776-9786. Southon A, Greenough MA, Ganio G, Bush AI, Burke R, Camakaris J (2013) Presenilin Promotes Dietary Copper Uptake. PLoS One 8, e62811. Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek D (1987) Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science 235, 877-880. Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2, a006270. Multhaup G, Schlicksupp A, Hesse L, Beher D, Ruppert T, Masters CL, Beyreuther K (1996) The amyloid precursor protein of Alzheimer's disease in the reduction of copper (II) to copper (I). Science 271, 1406-1409. Barnham KJ, McKinstry WJ, Multhaup G, Galatis D, Morton CJ, Curtain CC, Williamson NA, White AR, Hinds MG, Norton RS (2003) Structure of the Alzheimer's disease amyloid precursor protein copper binding domain A regulator of neuronal copper homeostasis. J Biol Chem 278, 17401-17407. Reinhard C, Hébert SS, De Strooper B (2005) The amyloid-β precursor protein: integrating structure with biological function. The EMBO journal 24, 3996-4006. Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA (2010) Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142, 857-867. O’Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 34, 185. Hatori Y, Lutsenko S (2013) An expanding range of functions for the copper chaperone/antioxidant protein Atox1. Antioxid Redox Sign 19, 945-957. SEIDEL J, BIRK MØLLER L, MENTZEL H-J, KAUF E, VOGT S, PATZER S, WOLLINA U, ZINTL F, HORN N (2001) Disturbed copper transport in humans. Part 1: mutations of the ATP7A gene lead to Menkes disease and occipital horn syndrome. Cell Mol Biol 47, OL141-OL148. Tümer Z, Møller LB (2009) Menkes disease. Eur J Hum Genet 18, 511-518. Kaler SG (2011) ATP7A-related copper transport diseases—emerging concepts and future trends. Nat Rev Neurol 7, 15-29. Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW (1993) The Wilson disease gene is a putative copper transporting P–type ATPase similar to the Menkes gene. Nat Genet 5, 327-337. Lutsenko S, Gupta A, Burkhead JL, Zuzel V (2008) Cellular multitasking: the dual role of human Cu-ATPases in cofactor delivery and intracellular copper balance. Arch Biochem Biophys 476, 22-32. Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML (2007) Wilson's disease. The Lancet 369, 397-408. Gray EH, De Vos KJ, Dingwall C, Perkinton MS, Miller CC (2010) Deficiency of the copper chaperone for superoxide dismutase increases amyloid-β production. J Alzheimers Dis 21, 1101-1105. Murakami K, Murata N, Noda Y, Tahara S, Kaneko T, Kinoshita N, Hatsuta H, Murayama S, Barnham KJ, Irie K (2011) SOD1 (copper/zinc superoxide dismutase) deficiency drives amyloid β protein oligomerization and memory loss in mouse model of Alzheimer disease. J Biol Chem 286, 44557-44568. Lutsenko S (2010) Human copper homeostasis: a network of interconnected pathways. Curr Opin Chem Biol 14, 211-217. Robinson NJ, Winge DR (2010) Copper metallochaperones. Annu Rev Biochem 79, 537-562. Horn D, Barrientos A (2008) Mitochondrial copper metabolism and delivery to cytochrome c oxidase. IUBMB life 60, 421-429. Maxfield AB, Heaton DN, Winge DR (2004) Cox17 is functional when tethered to the mitochondrial inner membrane. J Biol Chem 279, 5072-5080. Glerum DM, Shtanko A, Tzagoloff A (1996) Characterization of COX17, a yeast gene involved in copper metabolism and assembly of cytochrome oxidase. J Biol Chem 271, 1450414509. Christie L-A, Su JH, Tu CH, Dick MC, Zhou J, Cotman CW (2007) Differential regulation of inhibitors of apoptosis proteins in Alzheimer’s disease brains. Neurobiol Dis 26, 165-173. Mufti AR, Burstein E, Csomos RA, Graf PC, Wilkinson JC, Dick RD, Challa M, Son J-K, Bratton SB, Su GL (2006) XIAP Is a copper binding protein deregulated in Wilson's disease and other copper toxicosis disorders. Mol Cell 21, 775-785. Mufti AR, Burstein E, Duckett CS (2007) XIAP: cell death regulation meets copper homeostasis. Arch Biochem Biophys 463, 168-174. Sanokawa-Akakura R, Cao W, Allan K, Patel K, Ganesh A, Heiman G, Burke R, Kemp FW, Bogden JD, Camakaris J (2010) Control of Alzheimer's amyloid beta toxicity by the high molecular weight immunophilin FKBP52 and copper homeostasis in Drosophila. PLoS One 5, e8626. Sanokawa-Akakura R, Dai H, Akakura S, Weinstein D, Fajardo JE, Lang SE, Wadsworth S, Siekierka J, Birge RB (2004) A novel role for the immunophilin FKBP52 in copper transport. J Biol Chem 279, 27845-27848. Santpere G, Nieto M, Puig B, Ferrer I (2006) Abnormal Sp1 transcription factor expression in Alzheimer disease and tauopathies. Neurosci Lett 397, 30-34. Citron BA, Dennis JS, Zeitlin RS, Echeverria V (2008) Transcription factor Sp1 dysregulation in Alzheimer's disease. J Neurosci Res 86, 2499-2504. Yu HT, Chan WWL, Chai KH, Lee CWC, Chang RCC, Yu MS, McLoughlin DM, Miller CC, Lau KF (2010) Transcriptional regulation of human FE65, a ligand of Alzheimer's disease amyloid precursor protein, by Sp1. J Cell Biochem 109, 782-793.

[72] [73] [74] [75] [76] [77] [78] [79]

Liang ZD, Tsai W-B, Lee M-Y, Savaraj N, Kuo MT (2012) Specificity protein 1 (sp1) oscillation is involved in copper homeostasis maintenance by regulating human high-affinity copper transporter 1 expression. Mol Pharmacol 81, 455-464. Vašák M, Meloni G (2011) Chemistry and biology of mammalian metallothioneins. J Biol Inorg Chem 16, 1067-1078. Tapiero H, Tew KD (2003) Trace elements in human physiology and pathology: zinc and metallothioneins. Biomed Pharmacother 57, 399-411. Vasˇak M, Meloni G (2009) Metallothionein-3, zinc, and copper in the central nervous system. Metallothioneins and related chelators Metal ions in life sciences 5, 319-352. Capdevila M, Bofill R, Palacios O, Atrian S (2012) State-of-the-art of metallothioneins at the beginning of the 21st century. Coordin Chem Rev 256, 46-62. Leary SC (2010) Redox regulation of SCO protein function: controlling copper at a mitochondrial crossroad. Antioxid Redox Sign 13, 1403-1416. Tao TY, Liu F, Klomp L, Wijmenga C, Gitlin JD (2003) The copper toxicosis gene product Murr1 directly interacts with the Wilson disease protein. J Biol Chem 278, 41593-41596. de Bie P, van de Sluis B, Burstein E, van de Berghe PV, Muller P, Berger R, Gitlin JD, Wijmenga C, Klomp LW (2007) Distinct Wilson’s disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B. Gastroenterology 133, 1316-1326.

Supplementary Table 3. Homeostatic Machinery Of Zinc Metabolism With A Link To Alzheimer’s Disease And Other Associated Disorders

Protein

Protein abbreviation

Gene (Human Chromosomal location)

Function in Zinc Metabolism

Link with Alzheimer’s Disease

Associated disorders in Zn Metabolism

Ref

Zinc Transport and Uptake Zrt- Irt- like proteins (Solute-Linked Carrier 39 family) Principle Function: Increasing Cytoplasmic Concentration of Zinc

ZIP1

SLC39A1 (1q21)

Plasma membrane zinc importer

Unknown

Prostate cancer

[2-6]

(Altered Expressing pattern in the brains of Aβ42expressing flies[1])

ZIP2 ZIP3 ZIP4 ZIP5

SLC39A2 (14q11.2) SLC39A3 (19p13.3) SLC39A4 (8q24.3)

Plasma membrane zinc importer

Unknown

Carotid artery disease

[3, 7, 8]

Plasma membrane zinc importer

Unknown

Unknown

[4]

Intestinal Zinc Transporter

Unknown

[3, 9-14]

SLC39A5 (12q13.3)

Plasma membrane zinc importer

Unknown

Acrodermatitis enteropahica, Pancreatic cancer, glioma Acrodermatitis enteropahica (?)

[3, 15]

ZIP6

SLC39A6 (18q12.2)

Plasma membrane zinc importer (immune cells); In mouse models Zip6 promoter gets methylated with age leading to Zn Dyshomeostasis in immune system[16]

Unknown

Breast cancer[17, 18]

ZIP7

SLC39A7 (6p21.3) SLC39A8 (4q22-q24)

ER into cytoplasm Zn exporter

Unknown

Breast cancer

[19, 20]

Plasma membrane zinc importer (along with Mn2+ and Cd2+)

Unknown

Unknown

[3, 21]

SLC39A9 (14q24.1) SLC39A10 (2q32.3)

Golgi into cytoplasm Zn exporter (immune system) Plasma membrane zinc importer (control of zinc homeostasis in brain and liver) Limited information available

Unknown

Unknown

[22-24]

Unknown

Breast cancer

[4, 25-27]

Unknown

Unknown

[28]

Limited information available

Neuroprotection by increasing intracellular Zn[29, 30] Unknown

Schizophrenia

[31, 32]

Ehlers-Danlos syndrome

[31, 33-35]

Unknown

Asthma, Hepatocellular Cancer

[31, 36-38]

ZIP8 ZIP9 ZIP10 ZIP11 ZIP12 ZIP13

SLC39A13 (11p11.2) SLC39A14 (8p21.3)

ER into cytoplasm Zn exporter, Glucose Homeostasis Plasma membrane zinc importer (along with Cd2+ and NBTI Fe), help Astrocytes scavenge Iron and Zinc

ZnT1

SLC30A1 (1q32.3)

Cellular export (in neurons) and import into Endoplasmic Reticulum (ER)

Increased in different ADaffected brain regions*[39, 40] and Senile Plaques[41]

Alzheimer’s disease, Pancreatic cancer

[3, 42, 43]

ZnT2

SLC30A2 (1p35.3)

Transporting Zn into secretory vesicles (e.g. Mammary Glands)

Unknown

Zinc Deficiency in a BreastFed Infant

[44, 45]

ZnT3

SLC30A3 (2p23.3)

Transporting Zn into secretory vesicles (e.g. Brain), Concentrates Zn2+ ions in presynaptic. ZnT3 expression increases with age[46]

Synaptic and memory deficits in AD[47, 48]

Alzheimer’s disease, decreased in AD-affected brain regions

[44, 49]

ZnT4

SLC30A4 (15q21.1)

Transporting Zn into secretory vesicles, specifically the acidic ones

Increased in different ADaffected brain regions[39] and Senile Plaques[41]

Alzheimer’s disease

[50-52]

ZnT5

SLC30A5 (5q12.1)

Intestinal basolateral membrane transporter, transporter of Zn into Golgi and trans-Golgi network

Enriched in Aβ positive plaques[41]

Osteopenia

[53, 54]

ZIP14

Zn Transporters (Solute-Linked Carrier 30 family) Principle Function: decreasing Cytoplasmic Concentration of Zinc

SLC39A11 (17q21.31) SLC39A12 (10p12.33)

ZnT6 ZnT7 ZnT8

ZnT9 ZnT10

Albumin

Alb

α2-macroglobulin

SLC30A6 (2p22.3) SLC30A7 (1p21.2) SLC30A8 (8q24.11)

Transport into Golgi/TGN

SLC30A9 (4p13) SLC30A10 (1q41)

Limited information available

Transport into Golgi/TGN Transporting Zn into secretory vesicles (e.g. Pancreatic β cells)

Limited information available

Increased in different ADaffected brain regions[39, 55] Unknown

Alzheimer’s disease

[44, 56]

Prostate cancer

[57-59]

Unknown; Ischemic injuries reduce expression of ZnT8, the same hypothesis might be valid in case of AD(?)[60] Unknown

Type I and II diabetes mellitus

[61-65]

Unknown

[3, 44]

Abnormal levels of ZnT10 mRNA expression[66]

Parkinson’s disease, dystonia, hypermanganesemia, hepatic cirrhosis,

[67, 68]

Alb (4q13.3)

Intestine to liver and systemic zinc carrier

Serum Albumin is reduced in AD patients[69]

Unknown

[70]

A2M

A2M (12p13.31)

Intestine to liver and systemic zinc carrier

Unknown

[73]

Na+/Ca2+ exchanger

NCX1

NCX1 (2p23-p22)

Putative neuron Zn transporter; Depends upon Na+ gradient

• A2M is not associated with AD in Han Chinese population [71] • Involved in Aβ clearance[72] • Increased levels is reported in parietal cortex of AD[74] • A variation alters the age of EOAD[75]

Ischemia, Cardiac hypertrophy

[76-78]

AMPAR Ca–Zn receptors

AMPAR (PDB 3KG2)

---

Main neuronal Zn uptake channel; in case of acidic medium is highly permeable ionotropic glutamate receptor to Ca2+ and Zn2+ in neurons and oligodendrocytes[79]

Unknown

[81-83]

Ca2+ through VGCC proposed to involved in Aβ-induced neuronal injury[84] See Copper metabolism table

Calcium channelopathies

[85, 86]

Alzheimer’s Disease

[87]

Proposed to be involved in Ca2+ dyshomeostasis in AD pathobiology[88, 89]

Unknown

[52]

Unknown

Unknown

[90, 91]

L- and N-type Voltagegated Ca2+

VGCC

---

Main neuronal Zn uptake channel

Presenilin1, 2

PSEN1, 2

PSEN1 (14q24.3) PSEN2 (1q31-q42)

Promote zinc Uptake to tissue specifically the brain

Transient receptor potential mucolipin 1

TRPML1

Mucolipin-1 (19p13.2)

Lysosomal Zinc Transporter

Metal- response element (MRE)–binding transcription factor 1

MTF1

Altered post transcriptional modulation in prefrontal cortex of AD Patients[80]

Zinc Cellular Regulatory Machinery MTF1 (1p33)

Master regulatory transcription factor, Zinc ion sensor

Metal- response element (MRE)–binding transcription factor 2

MTF2

MTF2 (1p22.1)

Involved in stem cell development

Unknown

[92]

Amyloid β precursor protein

APP

APP (21q21.3)

Involved in brain Zn Homeostasis

See Iron Metabolism Table

Unknown

[93]

Metallothionein-1

MT1 (Subtypes A, B, E, F, G, H, L, M, X)

---

Zn2+ buffering Peptide: Controlling zinc availability (as both being zinc acceptors or being zinc donors), act as a redox proteins,

Increased in astrocytes of postmortem AD brain[94]

Unknown

[95-97]

Metallothionein-2

MT2

MT2A (16q13)

Zn2+ buffering Peptide: controlling zinc availability (as both being zinc acceptors or being zinc donors), Delivers Zn to Cellular compartments

Increased in astrocytes of postmortem AD brain[94]

Unknown

[97-99]

Metallothionein-3

MT3

MT3 (16q13)

Neuronal growth inhibitory factor Restricted tissue expression (Expressed in the Brain in both neurons and astrocyte). MT-3 interacts with small GTPase-protein Rab3a to induce a pathway of Zn reuptake into synaptic vesicles. MT-3 is involved in brain Cu and Zn homeostasis.

Down-regulated in AD brain[100]

Alzheimer’s disease

[97, 101104]

Metallothionein-4

MT4

MT4 (16q13)

Zn2+ buffering Peptide, Restricted tissue expression (expressed in squamous epithelia)

Unknown

Unknown

[97, 103]

Unknown

Zinc Storage Machinery

* Despite the paramount influence of hypothalamic-pituitary-gonadal (HPG) axis hormones during ageing as a potential mechanism of promoting neurodegeneration[105-107], to the best of our knowledge the only direct relation of this axis to the hypothesis of MCs is the significant decrease of the ZnT1 channel in HPG of mild cognitive impairment(MCI) subjects and interesting increase of this Zn transporter in HPG of early AD as well as late AD subjects. This correlation in parallel to the absolute neuromodulatory role of Zn ion in CNS[108, 109], further gives prominence to our hypothesis.

Table References: [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]

Lang M, Wang L, Fan Q, Xiao G, Wang X, Zhong Y, Zhou B (2012) Genetic inhibition of solute-linked carrier 39 family transporter 1 ameliorates aβ pathology in a Drosophila model of Alzheimer's disease. PLoS Genet 8, e1002683. Dempski RE (2012) The Cation Selectivity of the ZIP Transporters. Metal Transporters 69, 221. Lichten LA, Cousins RJ (2009) Mammalian zinc transporters: nutritional and physiologic regulation. Annu Rev Nutr 29, 153-176. Cousins RJ, Lichten LA (2011) Zinc Transporters, Rink L, ed. IOS press, pp. 136-162. Franklin RB, Feng P, Milon B, Desouki MM, Singh KK, Kajdacsy-Balla A, Bagasra O, Costello LC (2005) hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer. Mol Cancer 4, 32. Costello LC, Franklin RB (2006) The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots. Mol Cancer 5, 17. Giacconi R, Muti E, Malavolta M, Cardelli M, Pierpaoli S, Cipriano C, Costarelli L, Tesei S, Saba V, Mocchegiani E (2008) A novel Zip2 Gln/Arg/Leu codon 2 polymorphism is associated with carotid artery disease in aging. Rejuv Res 11, 297-300. Peters JL, Dufner‐Beattie J, Xu W, Geiser J, Lahner B, Salt DE, Andrews GK (2007) Targeting of the mouse Slc39a2 (Zip2) gene reveals highly cell‐specific patterns of expression, and unique functions in zinc, iron, and calcium homeostasis. Genesis 45, 339-352. Schmitt S, Küry S, Giraud M, Dréno B, Kharfi M, Bézieau S (2009) An update on mutations of the SLC39A4 gene in acrodermatitis enteropathica. Hum Mutat 30, 926-933. Li M, Zhang Y, Bharadwaj U, Zhai QJ, Ahern CH, Fisher WE, Brunicardi FC, Logsdon CD, Chen C, Yao Q (2009) Down-regulation of ZIP4 by RNA interference inhibits pancreatic cancer growth and increases the survival of nude mice with pancreatic cancer xenografts. Clin Cancer Res 15, 5993-6001. Li M, Zhang Y, Liu Z, Bharadwaj U, Wang H, Wang X, Zhang S, Liuzzi JP, Chang S-M, Cousins RJ (2007) Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression. P Natl Acad Sci Usa 104, 18636-18641. Zhang Y, Bharadwaj U, Logsdon CD, Chen C, Yao Q, Li M (2010) ZIP4 regulates pancreatic cancer cell growth by activating IL-6/STAT3 pathway through zinc finger transcription factor CREB. Clin Cancer Res 16, 1423-1430. Lin Y, Chen Y, Wang Y, Yang J, Zhu VF, Liu Y, Cui X, Chen L, Yan W, Jiang T (2013) ZIP4 is a novel molecular marker for glioma. Neuro-oncology. Antala S, Dempski RE (2012) The human ZIP4 transporter has two distinct binding affinities and mediates transport of multiple transition metals. Biochemistry 51, 963-973. Wang F, Kim B-E, Petris MJ, Eide DJ (2004) The mammalian Zip5 protein is a zinc transporter that localizes to the basolateral surface of polarized cells. J Biol Chem 279, 5143351441. Wong CP, Magnusson KR, Ho E (2013) Increased inflammatory response in aged mice is associated with age-related zinc deficiency and zinc transporter dysregulation. J Nutr Biochem 24, 353-359. Taylor KM, Morgan HE, Smart K, Zahari NM, Pumford S, Ellis IO, Robertson JF, Nicholson RI (2007) The emerging role of the LIV-1 subfamily of zinc transporters in breast cancer. Mol Med 13, 396. Taylor K (2008) A distinct role in breast cancer for two LIV-1 family zinc transporters. Biochem Soc T 36, 1247-1251. Hogstrand C, Kille P, Nicholson R, Taylor K (2009) Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation. Trends Mol Med 15, 101-111. Huang L, Kirschke CP, Zhang Y, Yu YY (2005) The ZIP7 gene (Slc39a7) encodes a zinc transporter involved in zinc homeostasis of the Golgi apparatus. J Biol Chem 280, 1545615463. He L, Girijashanker K, Dalton TP, Reed J, Li H, Soleimani M, Nebert DW (2006) ZIP8, member of the solute-carrier-39 (SLC39) metal-transporter family: characterization of transporter properties. Mol Pharmacol 70, 171-180. Matsuura W, Yamazaki T, Yamaguchi-Iwai Y, Masuda S, Nagao M, Andrews GK, Kambe T (2009) SLC39A9 (ZIP9) regulates zinc homeostasis in the secretory pathway: characterization of the ZIP subfamily I protein in vertebrate cells. Biosci Biotech Bioch 73, 1142-1148. Schmitt-Ulms G, Ehsani S, Watts JC, Westaway D, Wille H (2009) Evolutionary descent of prion genes from the ZIP family of metal ion transporters. PLoS One 4, e7208. Taniguchi M, Fukunaka A, Hagihara M, Watanabe K, Kamino S, Kambe T, Enomoto S, Hiromura M (2013) Essential Role of the Zinc Transporter ZIP9/SLC39A9 in Regulating the Activations of Akt and Erk in B-Cell Receptor Signaling Pathway in DT40 Cells. PLoS One 8, e58022. Kaler P, Prasad R (2007) Molecular cloning and functional characterization of novel zinc transporter rZip10 (Slc39a10) involved in zinc uptake across rat renal brush-border membrane. Am J Physiol-Renal 292, F217-F229. Kagara N, Tanaka N, Noguchi S, Hirano T (2007) Zinc and its transporter ZIP10 are involved in invasive behavior of breast cancer cells. Cancer science 98, 692-697. Lichten LA, Ryu M-S, Guo L, Embury J, Cousins RJ (2011) MTF-1-mediated repression of the zinc transporter Zip10 is alleviated by zinc restriction. PLoS One 6, e21526.

[28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55]

Kelleher SL, Velasquez V, Croxford TP, McCormick NH, Lopez V, MacDavid J (2012) Mapping the zinc‐transporting system in mammary cells: Molecular analysis reveals a phenotype‐dependent zinc‐transporting network during lactation. J Cell Physiol 227, 1761-1770. Crouch PJ, Savva MS, Hung LW, Donnelly PS, Mot AI, Parker SJ, Greenough MA, Volitakis I, Adlard PA, Cherny RA (2011) The Alzheimer’s therapeutic PBT2 promotes amyloid‐ β degradation and GSK3 phosphorylation via a metal chaperone activity. J Neurochem 119, 220-230. Chowanadisai W, Graham DM, Keen CL, Rucker RB, Messerli MA (2013) Neurulation and neurite extension require the zinc transporter ZIP12 (slc39a12). P Natl Acad Sci Usa 110, 9903-9908. Jeong J, Eide DJ (2013) The SLC39 family of zinc transporters. Mol Aspects Med 34, 612-619. Bly M (2006) Examination of the zinc transporter gene, SLC39A12. Schizophr Res 81, 321-322. Bin B-H, Fukada T, Hosaka T, Yamasaki S, Ohashi W, Hojyo S, Miyai T, Nishida K, Yokoyama S, Hirano T (2011) Biochemical Characterization of Human ZIP13 Protein A HomoDimerized Zinc Transporter Involved In The Spondylocheiro Dysplastic Ehlers-Danlos Syndrome. J Biol Chem 286, 40255-40265. Jeong J, Walker JM, Wang F, Park JG, Palmer AE, Giunta C, Rohrbach M, Steinmann B, Eide DJ (2012) Promotion of vesicular zinc efflux by ZIP13 and its implications for spondylocheiro dysplastic Ehlers–Danlos syndrome. P Natl Acad Sci Usa 109, E3530-E3538. Aydemir TB, Chang S-M, Guthrie GJ, Maki AB, Ryu M-S, Karabiyik A, Cousins RJ (2012) Zinc Transporter ZIP14 Functions in Hepatic Zinc, Iron and Glucose Homeostasis during the Innate Immune Response (Endotoxemia). PLoS One 7, e48679. Girijashanker K, He L, Soleimani M, Reed JM, Li H, Liu Z, Wang B, Dalton TP, Nebert DW (2008) Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities to the ZIP8 transporter. Mol Pharmacol 73, 1413-1423. Franklin RB, Levy BA, Zou J, Hanna N, Desouki MM, Bagasra O, Johnson LA, Costello LC (2012) ZIP14 zinc transporter downregulation and zinc depletion in the development and progression of hepatocellular cancer. J Gastrointest Cancer 43, 249-257. Bishop GM, Scheiber IF, Dringen R, Robinson SR (2010) Synergistic accumulation of iron and zinc by cultured astrocytes. J Neural Transm 117, 809-817. Lyubartseva G, Smith JL, Markesbery WR, Lovell MA (2010) Alterations of Zinc Transporter Proteins ZnT‐1, ZnT‐4 and ZnT‐6 in Preclinical Alzheimer's Disease Brain. Brain Pathol 20, 343-350. Lyubartseva G, Lovell MA (2012) A potential role for zinc alterations in the pathogenesis of Alzheimer's disease. Biofactors 38, 98-106. Zhang L-H, Wang X, Stoltenberg M, Danscher G, Huang L, Wang Z-Y (2008) Abundant expression of zinc transporters in the amyloid plaques of Alzheimer's disease brain. Brain Res Bull 77, 55-60. Lovell MA, Smith JL, Xiong S, Markesbery WR (2005) Alterations in zinc transporter protein-1 (ZnT-1) in the brain of subjects with mild cognitive impairment, early, and late-stage Alzheimer’s disease. Neurotox Res 7, 265-271. Lovell MA (2009) A potential role for alterations of zinc and zinc transport proteins in the progression of Alzheimer's disease. J Alzheimers Dis 16, 471-483. Huang L, Tepaamorndech S (2013) The SLC30 family of zinc transporters–A review of current understanding of their biological and pathophysiological roles. Mol Aspects Med 34, 548-560. Itsumura N, Inamo Y, Okazaki F, Teranishi F, Narita H, Kambe T, Kodama H (2013) Compound Heterozygous Mutations in SLC30A2/ZnT2 Results in Low Milk Zinc Concentrations: A Novel Mechanism for Zinc Deficiency in a Breast-Fed Infant. PLoS One 8, e64045. Saito T, Takahashi K, Nakagawa N, Hosokawa T, Kurasaki M, Yamanoshita O, Yamamoto Y, Sasaki H, Nagashima K, Fujita H (2000) Deficiencies of hippocampal Zn and ZnT3 accelerate brain aging of Rat. Biochem Bioph Res Co 279, 505-511. Adlard PA, Parncutt JM, Finkelstein DI, Bush AI (2010) Cognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer's disease? J Neurosci 30, 1631-1636. Rovelet-Lecrux A, Legallic S, Wallon D, Flaman J-M, Martinaud O, Bombois S, Rollin-Sillaire A, Michon A, Le Ber I, Pariente J (2011) A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease. Eur J Hum Genet 20, 613-617. Beyer N, Coulson D, Heggarty S, Ravid R, Irvine GB, Hellemans J, Johnston JA (2009) ZnT3 mRNA levels are reduced in Alzheimer’s disease post-mortem brain. Mol Neurodegener 4, 53. Kelleher SL, Lönnerdal B (2002) Zinc transporters in the rat mammary gland respond to marginal zinc and vitamin A intakes during lactation. The Journal of nutrition 132, 32803285. McCormick NH, Kelleher SL (2012) ZnT4 provides zinc to zinc-dependent proteins in the trans-Golgi network critical for cell function and Zn export in mammary epithelial cells. Am J Physiol-Cell Ph 303, C291-C297. Ira K, Jeffrey KL, Jessica RC, Shannon LK, Kirill K (2013) Zinc-Dependent Lysosomal Enlargement in TRPML1-Deficient Cells Involves MTF-1 Transcription Factor and ZnT4 (Slc30a4) Transporter. Biochem J 451, 155-163. Kambe T, Narita H, Yamaguchi-Iwai Y, Hirose J, Amano T, Sugiura N, Sasaki R, Mori K, Iwanaga T, Nagao M (2002) Cloning and characterization of a novel mammalian zinc transporter, zinc transporter 5, abundantly expressed in pancreatic β cells. J Biol Chem 277, 19049-19055. Inoue K, Matsuda K, Itoh M, Kawaguchi H, Tomoike H, Aoyagi T, Nagai R, Hori M, Nakamura Y, Tanaka T (2002) Osteopenia and male-specific sudden cardiac death in mice lacking a zinc transporter gene, Znt5. Hum Mol Genet 11, 1775-1784. Lovell MA, Smith JL, Markesbery WR (2006) Elevated zinc transporter-6 in mild cognitive impairment, Alzheimer disease, and pick disease. J Neuropath Exp Neur 65, 489-498.

[56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86]

Huang L, Kirschke CP, Gitschier J (2002) Functional characterization of a novel mammalian zinc transporter, ZnT6. J Biol Chem 277, 26389-26395. Kirschke CP, Huang L (2003) ZnT7, a novel mammalian zinc transporter, accumulates zinc in the Golgi apparatus. J Biol Chem 278, 4096-4102. Kolenko V, Teper E, Kutikov A, Uzzo R (2013) Zinc and zinc transporters in prostate carcinogenesis. Nat Rev Urol 10, 219-226. Tepaamorndech S, Huang L, Kirschke CP (2011) A null-mutation in the Znt7 gene accelerates prostate tumor formation in a transgenic adenocarcinoma mouse prostate model. Cancer Let 308, 33-42. DeNiro M, Al-Mohanna FA (2012) Zinc transporter 8 (znt8) expression is reduced by ischemic insults: A potential therapeutic target to prevent ischemic retinopathy. PLoS One 7, e50360. Chimienti F, Devergnas S, Pattou F, Schuit F, Garcia-Cuenca R, Vandewalle B, Kerr-Conte J, Van Lommel L, Grunwald D, Favier A (2006) In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion. J Cell Sci 119, 4199-4206. Wijesekara N, Dai F, Hardy A, Giglou P, Bhattacharjee A, Koshkin V, Chimienti F, Gaisano H, Rutter G, Wheeler M (2010) Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 53, 1656-1668. Fu Y, Tian W, Pratt EB, Dirling LB, Shyng S-L, Meshul CK, Cohen DM (2009) Down-regulation of ZnT8 expression in INS-1 rat pancreatic beta cells reduces insulin content and glucose-inducible insulin secretion. PLoS One 4, e5679. Rutter GA (2010) Think zinc: New roles for zinc in the control of insulin secretion. Islets 2, 49-50. Miao X, Sun W, Fu Y, Miao L, Cai L (2013) Zinc homeostasis in the metabolic syndrome and diabetes. F Med, 1-22. Bosomworth HJ, Adlard PA, Ford D, Valentine RA (2013) Altered Expression of ZnT10 in Alzheimer's Disease Brain. PLoS One 8, e65475. Tuschl K, Clayton PT, Gospe Jr SM, Gulab S, Ibrahim S, Singhi P, Aulakh R, Ribeiro RT, Barsottini OG, Zaki MS (2012) Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia Caused by Mutations in SLC30A10, a Manganese Transporter in Man. Am J Hum Genet 90, 457-466. Quadri M, Federico A, Zhao T, Breedveld GJ, Battisti C, Delnooz C, Severijnen L-A, Di Toro Mammarella L, Mignarri A, Monti L (2012) Mutations in SLC30A10 Cause Parkinsonism and Dystonia with Hypermanganesemia, Polycythemia, and Chronic Liver Disease. Am J Hum Genet 90, 467-477. Kim TS, Pae CU, Yoon SJ, Jang WY, Lee NJ, Kim JJ, Lee SJ, Lee C, Paik IH, Lee CU (2006) Decreased plasma antioxidants in patients with Alzheimer's disease. Int J Geriatr Psych 21, 344-348. Gibson RS, Hess SY, Hotz C, Brown KH (2008) Indicators of zinc status at the population level: a review of the evidence. Br J Nutr 99, S14-23. Bian L, Yang JD, Guo TW, Duan Y, Qin W, Sun Y, Feng GY, He L (2005) Association Study of the A2M and LRP1Genes with Alzheimer Disease in the Han Chinese. Biol Psychiat 58, 731-737. Tanzi RE, Bertram L (2005) Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 120, 545-555. Mills C (1989) The biological significance of zinc for man: problems and prospects In Zinc in Human Biology Springer, pp. 371-381. Sokolow S, Luu SH, Headley AJ, Hanson AY, Kim T, Miller CA, Vinters HV, Gylys KH (2011) High levels of synaptosomal Na+ Ca2+ exchangers (NCX1, NCX2, NCX3) co-localized with amyloid-beta in human cerebral cortex affected by Alzheimer's disease. Cell Calcium 49, 208-216. Bi X-H, Lu C-M, Liu Q, Zhang Z-X, Zhao H-L, Yu J, Zhang J-W (2012) A 14 bp indel variation in the NCX1 gene modulates the age at onset in late-onset Alzheimer’s disease. J Neural Transm 119, 383-386. Ohana E, Segal D, Palty R, Ton-That D, Moran A, Sensi SL, Weiss JH, Hershfinkel M, Sekler I (2004) A sodium zinc exchange mechanism is mediating extrusion of zinc in mammalian cells. J Biol Chem 279, 4278-4284. Koo Hwang I, Yoo K-Y, Won Kim D, Kang T-C, Young Choi S, Kwon Y-G, Hee Han B, Sung Kim J, Won MH (2006) Na+/Ca2+ exchanger 1 alters in pyramidal cells and expresses in astrocytes of the gerbil hippocampal CA1 region after ischemia. Brain Res 1086, 181-190. Menick DR, Xu L, Kappler C, Jiang W, Withers PR, Shepherd N, Conway SJ, Müller JG (2002) Pathways regulating Na+/Ca2+ exchanger expression in the heart. Ann Ny Acad Sci 976, 237-247. Mato S, Sánchez‐Gómez MV, Bernal‐Chico A, Matute C (2013) Cytosolic zinc accumulation contributes to excitotoxic oligodendroglial death. Glia 61, 750-764. Akbarian S, Smith MA, Jones EG (1995) Editing for an AMPA receptor subunit RNA in prefrontal cortex and striatum in Alzheimer's disease, Huntington's disease and schizophrenia. Brain Res 699, 297-304. Jia Y, Jeng JM, Sensi SL, Weiss JH (2002) Zn2+ currents are mediated by calcium‐permeable AMPA/Kainate channels in cultured murine hippocampal neurones. J Physiol 543, 3548. Frederickson CJ, Koh JY, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6, 449-462. Weiss JH, Hartley DM, Koh J-y, Choi DW (1993) AMPA receptor activation potentiates zinc neurotoxicity. Neuron 10, 43-49. Weiss JH, Pike CJ, Cotman CW (1994) Rapid Communication: Ca2+ Channel Blockers Attenuate β‐Amyloid Peptide Toxicity to Cortical Neurons in Culture. J Neurochem 62, 372375. Kerchner GA, Canzoniero LM, Yu SP, Ling C, Choi DW (2000) Zn2+ current is mediated by voltage‐gated Ca2+ channels and enhanced by extracellular acidity in mouse cortical neurones. J Physiol 528, 39-52. Bidaud I, Mezghrani A, Swayne LA, Monteil A, Lory P (2006) Voltage-gated calcium channels in genetic diseases. BBA Mol Cell Res 1763, 1169-1174.

[87] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109]

Greenough MA, Volitakis I, Li Q-X, Laughton K, Evin G, Ho M, Dalziel AH, Camakaris J, Bush AI (2011) Presenilins promote the cellular uptake of copper and zinc and maintain copper chaperone of SOD1-dependent copper/zinc superoxide dismutase activity. J Biol Chem 286, 9776-9786. Yamamoto S, Wajima T, Hara Y, Nishida M, Mori Y (2007) Transient receptor potential channels in Alzheimer's disease. BBA Mol Basis Dis 1772, 958-967. Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci 31, 454-463. Haase H, Rink L (2011) Zinc Signaling, Rink L, ed. IOS press, pp. 94-117. Cousins RJ, Liuzzi JP, Lichten LA (2006) Mammalian zinc transport, trafficking, and signals. J Biol Chem 281, 24085-24089. Walker E, Chang WY, Hunkapiller J, Cagney G, Garcha K, Torchia J, Krogan NJ, Reiter JF, Stanford WL (2010) Polycomb-like 2 associates with PRC2 and regulates transcriptional networks during mouse embryonic stem cell self-renewal and differentiation. Cell Stem Cell 6, 153-166. Adlard PA, Bush AI (2006) Metals and Alzheimer's disease. J Alzheimers Dis 10, 145-163. 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, 349356. Palacios Ò, Atrian S, Capdevila M (2011) Zn-and Cu-thioneins: a functional classification for metallothioneins? J Biol Inorg Chem 16, 991-1009. Babula P, Masarik M, Adam V, Eckschlager T, Stiborova M, Trnkova L, Skutkova H, Provaznik I, Hubalek J, Kizek R (2012) Mammalian metallothioneins: properties and functions. Metallomics 4, 739-750. Zatta P (2008) Metallothioneins in biochemistry and pathology, World Scientific. Tapiero H, Tew KD (2003) Trace elements in human physiology and pathology: zinc and metallothioneins. Biomed Pharmacother 57, 399-411. Li Y, Maret W (2008) Human metallothionein metallomics. J Anal Atomic Spectrom 23, 1055-1062. Hozumi I, Asanuma M, Yamada M, Uchida Y (2004) Metallothioneins and neurodegenerative diseases. J Health Sci 50, 323-331. Bolognin S, Zatta P (2008) Metallothioneins And Neurodegenerative Diseases. Metallothioneins in biochemistry and pathology Singapore, London: World Scientific, 47-70. 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. Vašák M, Meloni G (2011) Chemistry and biology of mammalian metallothioneins. J Biol Inorg Chem 16, 1067-1078. Vasˇak M, Meloni G (2009) Metallothionein-3, zinc, and copper in the central nervous system. Metallothioneins and related chelators Metal ions in life sciences 5, 319-352. Atwood CS, Meethal SV, Liu T, Wilson AC, Gallego M, Smith MA, Bowen RL (2005) Dysregulation of the hypothalamic-pituitary-gonadal axis with menopause and andropause promotes neurodegenerative senescence. J Neuropath Exp Neur 64, 93-103. Meethal SV, Atwood C (2005) The role of hypothalamic-pituitary-gonadal hormones in the normal structure and functioning of the brain. Cell Mol Life Sci 62, 257-270. Atwood C (2005) Alzheimer’s disease: the impact of age-related changes in reproductive hormones. Cell Mol Life Sci 62, 255-256. Kay AR, Toth K (2008) Is zinc a neuromodulator? Sci Signal 1, re3. Sensi SL, Paoletti P, Bush AI, Sekler I (2009) Zinc in the physiology and pathology of the CNS. Nat Rev Neurosci 10, 780-791.