Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome

Journal of Experimental Medicine

Volumn 210, Issue 9, 2013, Pages 1779-1791

  Cozzi, Anna ^a   Santambrogio, Paolo ^a   Privitera, Daniela ^b   Broccoli, Vania ^a   Rotundo, Luisa Ida ^a   Garavaglia, Barbara ^c   Benz, Rudolf ^d   Altamura, Sandro ^e   Goede, Jeroen S ^f   Muckenthaler, Martina U ^e   Levi, Sonia ^a,b  

^a SAN RAFFAELE HOSPITAL   (Italy)

^b VITA SALUTE SAN RAFFAELE UNIVERSITY   (Italy)

^c Fondazione Istituto di Ricerca e Cura a Carattere Scientifico   (Italy)

^d Cantonal Hospital Thurgau Münsterlingen   (Switzerland)

^e UNIVERSITY OF HEIDELBERG   (Germany)

^f UNIVERSITY HOSPITAL ZURICH   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID; FERRITIN; IRON; REACTIVE OXYGEN METABOLITE;

ADULT; ARTICLE; CASE REPORT; CELL DAMAGE; CONTROLLED STUDY; FEMALE; FIBROBLAST; HUMAN; HUMAN CELL; IRON DEFICIENCY; LOSS OF FUNCTION MUTATION; MITOCHONDRIAL MEMBRANE POTENTIAL; OXIDATIVE STRESS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; RESTLESS LEGS SYNDROME; STOP CODON; TONIC CLONIC SEIZURE;

AMINO ACID SEQUENCE; APOFERRITINS; BASE SEQUENCE; CHILD; CODON, TERMINATOR; FEMALE; FIBROBLASTS; HALF-LIFE; HOMOZYGOTE; HUMANS; IRON; MEMBRANE POTENTIAL, MITOCHONDRIAL; MOLECULAR SEQUENCE DATA; NEURONS; OXIDATIVE STRESS; POLYMERIZATION; REACTIVE OXYGEN SPECIES; RECEPTORS, TRANSFERRIN; RESTLESS LEGS SYNDROME; SEIZURES; YOUNG ADULT;

EID: 84884258121     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20130315     Document Type: Article

References (78)

1. Allen, R. 2004. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med. 5:385-391. http://dx.doi.org/10.1016/ j.sleep.2004.01.012
2. Allen, R.P., and C.J. Earley. 2007. The role of iron in restless legs syndrome. Mov. Disord. 22(Suppl 18):S440-S448. http://dx.doi.org/10.1002/mds .21607
3. Allen, R.P., P.B. Barker, F. Wehrl, H.K. Song, and C.J. Earley. 2001. MRI measurement of brain iron in patients with restless legs syndrome. Neurology. 56:263-265. http://dx.doi.org/10.1212/WNL.56.2.263
4. Altamura, S., and M.U. Muckenthaler. 2009. Iron toxicity in diseases of aging: Alzheimer's disease, Parkinson's disease and atherosclerosis. J. Alzheimers Dis. 16:879-895.
5. Arosio, P., and S. Levi. 2010. Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage. Biochim. Biophys. Acta. 1800:783-792. http://dx.doi.org/10.1016/j.bbagen.2010 .02.005
6. Barzideh, O., R.G. Burright, and P.J. Donovick. 1995. Dietary iron and exposure to lead influence susceptibility to seizures. Psychol. Rep. 76:971-976. http://dx.doi.org/10.2466/pr0.1995.76.3.971
7. Beaumont, C., P. Leneuve, I. Devaux, J.Y. Scoazec, M. Berthier, M.N. Loiseau, B. Grandchamp, and D. Bonneau. 1995. Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract. Nat. Genet. 11:444-446. http://dx.doi.org/ 10.1038/ng1295-444
8. Berg, D., and M.B. Youdim. 2006. Role of iron in neurodegenerative disorders. Top. Magn. Reson. Imaging. 17:5-17. http://dx.doi.org/10.1097/ 01.rmr.0000245461.90406.ad
9. Brooks, D.G., K. Manova-Todorova, J. Farmer, L. Lobmayr, R.B. Wilson, R.C. Eagle Jr., T.G. St Pierre, and D. Stambolian. 2002. Ferritin crystal cataracts in hereditary hyperferritinemia cataract syndrome. Invest. Ophthalmol. Vis. Sci. 43:1121-1126.
10. Burn, J., and P.F. Chinnery. 2006. Neuroferritinopathy. Semin. Pediatr. Neurol. 13:176-181. http://dx.doi.org/10.1016/j.spen.2006.08.006
11. Caiazzo, M., M.T. Dell'Anno, E. Dvoretskova, D. Lazarevic, S. Taverna, D. Leo, T.D. Sotnikova, A. Menegon, P. Roncaglia, G. Colciago, et al. 2011. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature. 476:224-227. http://dx.doi.org/ 10.1038/nature10284
12. Campanella, A., E. Rovelli, P. Santambrogio, A. Cozzi, F. Taroni, and S. Levi. 2009. Mitochondrial ferritin limits oxidative damage regulating mitochondrial iron availability: hypothesis for a protective role in Friedreich ataxia. Hum. Mol. Genet. 18:1-11. http://dx.doi.org/10.1093/hmg/ddn308
13. Cho, Y.W., R.P. Allen, and C.J. Earley. 2013. Lower molecular weight intravenous iron dextran for restless legs syndrome. Sleep Med. 14:274-277. http://dx.doi.org/10.1016/j.sleep.2012.11.001
14. Clardy, S.L., X. Wang, W. Zhao, W. Liu, G.A. Chase, J.L. Beard, B. True Felt, and J.R. Connor. 2006. Acute and chronic effects of developmental iron deficiency on mRNA expression patterns in the brain. J. Neural Transm. Suppl. 71:173-196. http://dx.doi.org/10.1007/978-3-211-33328-0_19
15. Connor, J.R. 2008. Pathophysiology of restless legs syndrome: evidence for iron involvement. Curr. Neurol. Neurosci. Rep. 8:162-166. http:// dx.doi.org/10.1007/s11910-008-0026-x
16. Connor, J.R., P. Ponnuru, X.S. Wang, S.M. Patton, R.P. Allen, and C.J. Earley. 2011. Profile of altered brain iron acquisition in restless legs syndrome. Brain. 134:959-968. http://dx.doi.org/10.1093/brain/awr012
17. Cozzi, A., S. Levi, E. Bazzigaluppi, G. Ruggeri, and P. Arosio. 1989. Development of an immunoassay for all human isoferritins, and its application to serum ferritin evaluation. Clin. Chim. Acta. 184:197-206. http://dx.doi.org/10.1016/0009-8981(89)90052-1
18. Cozzi, A., B. Corsi, S. Levi, P. Santambrogio, A. Albertini, and P. Arosio. 2000. Overexpression of wild type and mutated human ferritin H-chain in HeLa cells: in vivo role of ferritin ferroxidase activity. J. Biol. Chem. 275:25122-25129. http://dx.doi.org/10.1074/jbc.M003797200
19. Cozzi, A., B. Corsi, S. Levi, P. Santambrogio, G. Biasiotto, and P. Arosio. 2004. Analysis of the biologic functions of H- and L-ferritins in HeLa cells by transfection with siRNAs and cDNAs: evidence for a proliferative role of L-ferritin. Blood. 103:2377-2383. http://dx.doi.org/10 .1182/blood-2003-06-1842
20. Cozzi, A., P. Santambrogio, B. Corsi, A. Campanella, P. Arosio, and S. Levi. 2006. Characterization of the l-ferritin variant 460InsA responsible of a hereditary ferritinopathy disorder. Neurobiol. Dis. 23:644-652. http:// dx.doi.org/10.1016/j.nbd.2006.05.004
21. Cozzi, A., E. Rovelli, G. Frizzale, A. Campanella, M. Amendola, P. Arosio, and S. Levi. 2010. Oxidative stress and cell death in cells expressing L-ferritin variants causing neuroferritinopathy. Neurobiol. Dis. 37:77-85. http:// dx.doi.org/10.1016/j.nbd.2009.09.009
22. Cremonesi, L., A. Cozzi, D. Girelli, F. Ferrari, I. Fermo, B. Foglieni, S. Levi, C. Bozzini, M. Camparini, M. Ferrari, and P. Arosio. 2004. Case report: a subject with a mutation in the ATG start codon of L-ferritin has no haematological or neurological symptoms. J. Med. Genet. 41:e81. http:// dx.doi.org/10.1136/jmg.2003.011718
23. Curtis, A.R., C. Fey, C.M. Morris, L.A. Bindoff, P.G. Ince, P.F. Chinnery, A. Coulthard, M.J. Jackson, A.P. Jackson, D.P. McHale, et al. 2001. Mutation in the gene encoding ferritin light polypeptide causes dominant adultonset basal ganglia disease. Nat. Genet. 28:350-354. http://dx.doi.org/ 10.1038/ng571
24. Daniells, S., and G. Hardy. 2010. Hair loss in long-term or home parenteral nutrition: are micronutrient deficiencies to blame? Curr. Opin. Clin. Nutr. Metab. Care. 13:690-697. http://dx.doi.org/10.1097/MCO .0b013e32833ece02
25. Darshan, D., L. Vanoaica, L. Richman, F. Beermann, and L.C. Kühn. 2009. Conditional deletion of ferritin H in mice induces loss of iron storage and liver damage. Hepatology. 50:852-860. http://dx.doi.org/10.1002/ hep.23058
26. De Domenico, I., D.M. Ward, and J. Kaplan. 2009. Specific iron chelators determine the route of ferritin degradation. Blood. 114:4546-4551. http:// dx.doi.org/10.1182/blood-2009-05-224188
27. Du, X., E. She, T. Gelbart, J. Truksa, P. Lee, Y. Xia, K. Khovananth, S. Mudd, N. Mann, E.M. Moresco, et al. 2008. The serine protease TMPRSS6 is required to sense iron deficiency. Science. 320:1088-1092. http://dx.doi.org/ 10.1126/science.1157121
28. Earley, C.J., P. B Barker, A. Horská, and R.P. Allen. 2006. MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome. Sleep Med. 7:458-461. http://dx.doi.org/10.1016/j.sleep .2005.11.009
29. Earley, C.J., A. Horská, M.A. Mohamed, P.B. Barker, J.L. Beard, and R.P. Allen. 2009. A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome. Sleep Med. 10:206-211. http://dx.doi.org/10.1016/j.sleep.2007.12.006
30. Ferreira, C., D. Bucchini, M.E. Martin, S. Levi, P. Arosio, B. Grandchamp, and C. Beaumont. 2000. Early embryonic lethality of H ferritin gene deletion in mice. J. Biol. Chem. 275:3021-3024. http://dx.doi.org/ 10.1074/jbc.275.5.3021
31. Ferreira, C., P. Santambrogio, M.E. Martin, V. Andrieu, G. Feldmann, D. Hénin, and C. Beaumont. 2001. H ferritin knockout mice: a model of hyperferritinemia in the absence of iron overload. Blood. 98:525-532. http://dx.doi.org/10.1182/blood.V98.3.525
32. Ford, G.C., P.M. Harrison, D.W. Rice, J.M. Smith, A. Treffry, J.L. White, and J. Yariv. 1984. Ferritin: design and formation of an iron-storage molecule. Philos. Trans. R. Soc. Lond. B Biol. Sci. 304:551-565. http://dx.doi .org/10.1098/rstb.1984.0046
33. Godau, J., U. Klose, A. Di Santo, K. Schweitzer, and D. Berg. 2008. Multiregional brain iron deficiency in restless legs syndrome. Mov. Disord. 23:1184-1187. http://dx.doi.org/10.1002/mds.22070
34. Hayflick, S.J. 2006. Neurodegeneration with brain iron accumulation: from genes to pathogenesis. Semin. Pediatr. Neurol. 13:182-185. http://dx.doi .org/10.1016/j.spen.2006.08.007
35. Hentze, M.W., M.U. Muckenthaler, B. Galy, and C. Camaschella. 2010. Two to tango: regulation of Mammalian iron metabolism. Cell. 142: 24-38. http://dx.doi.org/10.1016/j.cell.2010.06.028
36. Idro, R., S. Gwer, T.N. Williams, T. Otieno, S. Uyoga, G. Fegan, P.A. Kager, K. Maitland, F. Kirkham, B.G. Neville, and C.R. Newton. 2010. Iron deficiency and acute seizures: results from children living in rural Kenya and a meta-analysis. PLoS ONE. 5:e14001. http://dx.doi .org/10.1371/journal.pone.0014001
37. Isken, O., and L.E. Maquat. 2007. Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function. Genes Dev. 21:1833- 1856. http://dx.doi.org/10.1101/gad.1566807
38. Jeong, S.Y., D.R. Crooks, H. Wilson-Ollivierre, M.C. Ghosh, R. Sougrat, J. Lee, S. Cooperman, J.B. Mitchell, C. Beaumont, and T.A. Rouault. 2011. Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice. PLoS ONE. 6:e25404. http:// dx.doi.org/10.1371/journal.pone.0025404
39. Kannengiesser, C., A.M. Jouanolle, G. Hetet, A. Mosser, F. Muzeau, D. Henry, E. Bardou-Jacquet, M. Mornet, P. Brissot, Y. Deugnier, et al. 2009. A new missense mutation in the L ferritin coding sequence associated with elevated levels of glycosylated ferritin in serum and absence of iron overload. Haematologica. 94:335-339. http://dx.doi.org/ 10.3324/haematol.2008.000125
40. Kurtoglu, E., A. Ugur, A.K. Baltaci, and L. Undar. 2003. Effect of iron supplementation on oxidative stress and antioxidant status in irondeficiency anemia. Biol. Trace Elem. Res. 96:117-123. http://dx.doi .org/10.1385/BTER:96:1-3:117
41. Langlois d'Estaintot, B., P. Santambrogio, T. Granier, B. Gallois, J.M. Chevalier, G. Précigoux, S. Levi, and P. Arosio. 2004. Crystal structure and biochemical properties of the human mitochondrial ferritin and its mutant Ser144Ala. J. Mol. Biol. 340:277-293. http://dx.doi.org/ 10.1016/j.jmb.2004.04.036
42. Lawson, D.M., P.J. Artymiuk, S.J. Yewdall, J.M. Smith, J.C. Livingstone, A. Treffry, A. Luzzago, S. Levi, P. Arosio, G. Cesareni, et al. 1991. Solving the structure of human H ferritin by genetically engineering intermolecular crystal contacts. Nature. 349:541-544. http://dx.doi.org/ 10.1038/349541a0
43. Levi, S., and P. Arosio. 2004. Mitochondrial ferritin. Int. J. Biochem. Cell Biol. 36:1887-1889. http://dx.doi.org/10.1016/j.biocel.2003.10.020
44. Levi, S., A. Luzzago, G. Cesareni, A. Cozzi, F. Franceschinelli, A. Albertini, and P. Arosio. 1988. Mechanism of ferritin iron uptake: activity of the H-chain and deletion mapping of the ferro-oxidase site. A study of iron uptake and ferro-oxidase activity of human liver, recombinant H-chain ferritins, and of two H-chain deletion mutants. J. Biol. Chem. 263:18086-18092.
45. Levi, S., A. Luzzago, F. Franceschinelli, P. Santambrogio, G. Cesareni, and P. Arosio. 1989. Mutational analysis of the channel and loop sequences of human ferritin H-chain. Biochem. J. 264:381-388.
46. Levi, S., S.J. Yewdall, P.M. Harrison, P. Santambrogio, A. Cozzi, E. Rovida, A. Albertini, and P. Arosio. 1992. Evidence of H- and L-chains have co-operative roles in the iron-uptake mechanism of human ferritin. Biochem. J. 288:591-596.
47. Levi, S., P. Santambrogio, A. Cozzi, E. Rovida, B. Corsi, E. Tamborini, S. Spada, A. Albertini, and P. Arosio. 1994. The role of the L-chain in ferritin iron incorporation. Studies of homo and heteropolymers. J. Mol. Biol. 238:649-654. http://dx.doi.org/10.1006/jmbi.1994.1325
48. Levi, S., B. Corsi, M. Bosisio, R. Invernizzi, A. Volz, D. Sanford, P. Arosio, and J. Drysdale. 2001. A human mitochondrial ferritin encoded by an intronless gene. J. Biol. Chem. 276:24437-24440. http://dx.doi.org/10.1074/ jbc.C100141200
49. Levi, S., A. Cozzi, and P. Arosio. 2005. Neuroferritinopathy: a neurodegenerative disorder associated with L-ferritin mutation. Best Pract. Res. Clin. Haematol. 18:265-276. http://dx.doi.org/10.1016/j.beha.2004 .08.021
50. Lozoff, B., and M.K. Georgieff. 2006. Iron deficiency and brain development. Semin. Pediatr. Neurol. 13:158-165. http://dx.doi.org/10.1016/j.spen .2006.08.004
51. Luscieti, S., P. Santambrogio, B. Langlois d'Estaintot, T. Granier, A. Cozzi, M. Poli, B. Gallois, D. Finazzi, A. Cattaneo, S. Levi, and P. Arosio. 2010. Mutant ferritin L-chains that cause neurodegeneration act in a dominant- negative manner to reduce ferritin iron incorporation. J. Biol. Chem. 285:11948-11957. http://dx.doi.org/10.1074/jbc.M109.096404
52. Mehlhase, J., G. Sandig, K. Pantopoulos, and T. Grune. 2005. Oxidationinduced ferritin turnover in microglial cells: role of proteasome. Free Radic. Biol. Med. 38:276-285. http://dx.doi.org/10.1016/j.freeradbiomed.2004 .10.025
53. Millonig, G., M.U. Muckenthaler, and S. Mueller. 2010. Hyperferritinaemiacataract syndrome: worldwide mutations and phenotype of an increasingly diagnosed genetic disorder. Hum. Genomics. 4:250-262.
54. Missirlis, F., S. Kosmidis, T. Brody, M. Mavrakis, S. Holmberg, W.F. Odenwald, E.M. Skoulakis, and T.A. Rouault. 2007. Homeostatic mechanisms for iron storage revealed by genetic manipulations and live imaging of Drosophila ferritin. Genetics. 177:89-100. http://dx.doi.org/10 .1534/genetics.107.075150
55. Ozaydin, E., E. Arhan, B. Cetinkaya, S. Ozdel, A. Deg?erliyurt, A. Güven, and G. Köse. 2012. Differences in iron deficiency anemia and mean platelet volume between children with simple and complex febrile seizures. Seizure. 21:211-214. http://dx.doi.org/10.1016/j.seizure.2011.12.014
56. Picard, V., S. Epsztejn, P. Santambrogio, Z.I. Cabantchik, and C. Beaumont. 1998. Role of ferritin in the control of the labile iron pool in murine erythroleukemia cells. J. Biol. Chem. 273:15382-15386. http://dx.doi.org/10.1074/jbc.273.25.15382
57. Pigeolet, E., P. Corbisier, A. Houbion, D. Lambert, C. Michiels, M. Raes, M.D. Zachary, and J. Remacle. 1990. Glutathione peroxidase, superoxide dismutase, and catalase inactivation by peroxides and oxygen derived free radicals. Mech. Ageing Dev. 51:283-297. http://dx.doi .org/10.1016/0047-6374(90)90078-T
58. Rajendiran, S., B. Zachariah, and A. Hamide. 2012. Increased protein carbonylation and decreased antioxidant status in anemic H. pylori infected patients: effect of treatment. Saudi J. Gastroenterol. 18:252-256. http:// dx.doi.org/10.4103/1319-3767.98430
59. Recalcati, S., G. Minotti, and G. Cairo. 2010. Iron regulatory proteins: from molecular mechanisms to drug development. Antioxid. Redox Signal. 13:1593-1616. http://dx.doi.org/10.1089/ars.2009.2983
60. Romão, L., A. Inácio, S. Santos, M. Avila, P. Faustino, P. Pacheco, and J. Lavinha. 2000. Nonsense mutations in the human beta-globin gene lead to unexpected levels of cytoplasmic mRNA accumulation. Blood. 96:2895-2901.
61. Rouault, T.A., and S. Cooperman. 2006. Brain iron metabolism. Semin. Pediatr. Neurol. 13:142-148. http://dx.doi.org/10.1016/j.spen.2006.08.002
62. Salas, R.E., C.E. Gamaldo, and R.P. Allen. 2010. Update in restless legs syndrome. Curr. Opin. Neurol. 23:401-406.
63. Santambrogio, P., S. Levi, P. Arosio, L. Palagi, G. Vecchio, D.M. Lawson, S.J. Yewdall, P.J. Artymiuk, P.M. Harrison, R. Jappelli, et al. 1992. Evidence that a salt bridge in the light chain contributes to the physical stability difference between heavy and light human ferritins. J. Biol. Chem. 267:14077-14083.
64. Santambrogio, P., S. Levi, A. Cozzi, E. Rovida, A. Albertini, and P. Arosio. 1993. Production and characterization of recombinant heteropolymers of human ferritin H and L chains. J. Biol. Chem. 268:12744-12748.
65. Schulz, J.B., J. Lindenau, J. Seyfried, and J. Dichgans. 2000. Glutathione, oxidative stress and neurodegeneration. Eur. J. Biochem. 267:4904-4911. http://dx.doi.org/10.1046/j.1432-1327.2000.01595.x
66. Sherjil, A., Z. us Saeed, S. Shehzad, and R. Amjad. 2010. Iron deficiency anaemia-a risk factor for febrile seizures in children. J. Ayub Med. Coll. Abbottabad. 22:71-73.
67. Snyder, A.M., and J.R. Connor. 2009. Iron, the substantia nigra and related neurological disorders. Biochim. Biophys. Acta. 1790:606-614. http:// dx.doi.org/10.1016/j.bbagen.2008.08.005
68. Snyder, A.M., X. Wang, S.M. Patton, P. Arosio, S. Levi, C.J. Earley, R.P. Allen, and J.R. Connor. 2009. Mitochondrial ferritin in the substantia nigra in restless legs syndrome. J. Neuropathol. Exp. Neurol. 68:1193-1199. http:// dx.doi.org/10.1097/NEN.0b013e3181bdc44f
69. Sun, S., P. Arosio, S. Levi, and N.D. Chasteen. 1993. Ferroxidase kinetics of human liver apoferritin, recombinant H-chain apoferritin, and sitedirected mutants. Biochemistry. 32:9362-9369. http://dx.doi.org/10.1021/ bi00087a015
70. Thompson, K., S. Menzies, M. Muckenthaler, F.M. Torti, T. Wood, S.V. Torti, M.W. Hentze, J. Beard, and J. Connor. 2003. Mouse brains deficient in H-ferritin have normal iron concentration but a protein profile of iron deficiency and increased evidence of oxidative stress. J. Neurosci. Res. 71:46-63. http://dx.doi.org/10.1002/jnr.10463
71. Thurlow, V., B. Vadher, A. Bomford, C. DeLord, C. Kannengiesser, C. Beaumont, and B. Grandchamp. 2012. Two novel mutations in the L ferritin coding sequence associated with benign hyperferritinaemia unmasked by glycosylated ferritin assay. Ann. Clin. Biochem. 49:302-305. http://dx.doi.org/10.1258/acb.2011.011229
72. Trost, L.B., W.F. Bergfeld, and E. Calogeras. 2006. The diagnosis and treatment of iron deficiency and its potential relationship to hair loss. J. Am. Acad. Dermatol. 54:824-844. http://dx.doi.org/10.1016/j.jaad.2005.11 .1104
73. Vidal, R., B. Ghetti, M. Takao, C. Brefel-Courbon, E. Uro-Coste, B.S. Glazier, V. Siani, M.D. Benson, P. Calvas, L. Miravalle, et al. 2004. Intracellular ferritin accumulation in neural and extraneural tissue characterizes a neurodegenerative disease associated with a mutation in the ferritin light polypeptide gene. J. Neuropathol. Exp. Neurol. 63: 363-380.
74. Vierbuchen, T., and M. Wernig. 2011. Direct lineage conversions: unnatural but useful? Nat. Biotechnol. 29:892-907. http://dx.doi.org/10.1038/ nbt.1946
75. Wan, L., G. Nie, J. Zhang, and B. Zhao. 2012. Overexpression of human wild-type amyloid-? protein precursor decreases the iron content and increases the oxidative stress of neuroblastoma SH-SY5Y cells. J. Alzheimers Dis. 30:523-530.
76. White, C.W., D.H. Nguyen, K. Suzuki, N. Taniguchi, L.S. Rusakow, K.B. Avraham, and Y. Groner. 1993. Expression of manganese superoxide dismutase is not altered in transgenic mice with elevated level of copper-zinc superoxide dismutase. Free Radic. Biol. Med. 15:629-636. http://dx.doi .org/10.1016/0891-5849(93)90166-R
77. Yewdall, S.J., D.M. Lawson, P.J. Artymiuk, A. Treffry, P.M. Harrison, A. Luzzago, G. Cesareni, S. Levi, and P. Arosio. 1990. Structural studies on recombinant human ferritins. Biochem. Soc. Trans. 18:1028-1029.
78. Zhao, G., F. Bou-Abdallah, P. Arosio, S. Levi, C. Janus-Chandler, and N.D. Chasteen. 2003. Multiple pathways for mineral core formation in mammalian apoferritin. The role of hydrogen peroxide. Biochemistry. 42:3142- 3150. http://dx.doi.org/10.1021/bi027357