Iron and restless legs syndrome: treatment, genetics and pathophysiology

Sleep Medicine

Volumn 31, Issue , 2017, Pages 61-70

  Connor, James R ^a   Patton, Stephanie M ^a   Oexle, Konrad ^b,d   Allen, Richard P ^c  

^a PENN STATE MILTON S HERSHEY MEDICAL CENTER   (United States)

^b TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^c JOHNS HOPKINS UNIVERSITY   (United States)

^d INSTITUTE OF EPIDEMIOLOGY   (Germany)

Author keywords

Blood brain barrier; Dopamine; Genetics; Hypoxia; Iron; RLS

Indexed keywords

3 NITROTYROSINE; ADENOSINE; ANTIANEMIC AGENT; CYSTATIN C; DOPAMINE; FERRIC CARBOXYMALTOSE; FERRITIN; FERROUS GLUCONATE; HEMOGLOBIN BETA CHAIN; HISTONE DEMETHYLASE; HISTONE DEMETHYLASE B; HISTONE DEMETHYLASE C; HISTONE DEMETHYLASE KDM6A; HYPOXIA INDUCIBLE FACTOR; HYPOXIA INDUCIBLE FACTOR 1ALPHA; HYPOXIA INDUCIBLE FACTOR 2ALPHA; IRON; IRON DEXTRAN; IRON ISOMALTOSIDE; IRON REGULATORY PROTEIN 1; IRON SACCHARATE; NEURONAL NITRIC OXIDE SYNTHASE; NITRIC OXIDE; PROCOLLAGEN PROLINE 2 OXOGLUTARATE 4 DIOXYGENASE; PROSTAGLANDIN D2 SYNTHASE; SYNTHETASE; TRANSFERRIN RECEPTOR; UNCLASSIFIED DRUG; VASCULOTROPIN; VITAMIN D BINDING PROTEIN;

ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; ARTICLE; DOPAMINE BRAIN LEVEL; DOPAMINERGIC SYSTEM; ENZYME ACTIVITY; EPIGENETICS; GENE; GENE MUTATION; GENETIC VARIABILITY; HFE GENE; HOMEOSTASIS; HUMAN; INCIDENCE; IRON CHELATION; IRON DEFICIENCY; IRON THERAPY; NONHUMAN; PARKINSON DISEASE; PATHOPHYSIOLOGY; RESTLESS LEGS SYNDROME; ANIMAL; BRAIN; DRUG EFFECTS; GENETICS; METABOLISM;

ANIMALS; BRAIN; HUMANS; IRON; RESTLESS LEGS SYNDROME;

EID: 85008423152     PISSN: 13899457     EISSN: 18785506     Source Type: Journal    
DOI: 10.1016/j.sleep.2016.07.028     Document Type: Article

References (119)

1. [1] Hentze, M.W., Muckenthaler, M.U., Galy, B., Camaschella, C., Two to tango: regulation of Mammalian iron metabolism. Cell 142:1 (2010), 24–38.
2. [2] Muckenthaler, M.U., How mutant HFE causes hereditary hemochromatosis. Blood 124:8 (2014), 1212–1213.
3. [3] Earley, C.J., Connor, J.R., Beard, J.L., et al. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 54:8 (2000), 1698–1700.
4. [4] Mizuno, S., Mihara, T., Miyaoka, T., et al. CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res 14:1 (2005), 43–47.
5. [5] Akyol, A., Kiylioglu, N., Kadikoylu, G., et al. Iron deficiency anemia and restless legs syndrome: is there an electrophysiological abnormality?. Clin Neurol Neurosurg 106:1 (2003), 23–27.
6. [6] Allen, R.P., Auerbach, S., Bahrain, H., et al. The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 88:4 (2013), 261–264.
7. [7] Rangarajan, S., D'Souza, G.A., Restless legs syndrome in Indian patients having iron deficiency anemia in a tertiary care hospital. Sleep Med 8:3 (2007), 247–251.
8. [8] Aspenstroem, G., Pica and restless legs in iron deficiency. Sven Lakartidn 61 (1964), 1174–1177.
9. [9] Connor, J.R., Zhang, X., Nixon, A.M., et al. Comparative evaluation of nephrotoxicity and management by macrophages of intravenous pharmaceutical iron formulations. PLoS One, 10(5), 2015, e0125272.
10. [10] Unger, E.L., Earley, C.J., Thomsen, L.L., et al. Effects of IV iron isomaltoside-1000 treatment on regional brain iron status in an iron-deficient animal. Neuroscience 246 (2013), 179–185.
11. [11] Mehmood, T., Auerbach, M., Earley, C.J., et al. Response to intravenous iron in patients with iron deficiency anemia (IDA) and restless leg syndrome (Willis-Ekbom disease). Sleep Med 15:12 (2015), 1473–1476.
12. [12] Nordlander, N.B., Therapy in restless legs. Acta Med Scand 145:6 (1953), 453–457.
13. [13] Earley, C.J., Horska, A., Mohamed, M.A., et al. A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome. Sleep Med 10:2 (2009), 206–211.
14. [14] Cho, Y.W., Allen, R.P., Earley, C.J., Lower molecular weight intravenous iron dextran for restless legs syndrome. Sleep Med 14:3 (2013), 274–277.
15. [15] Grim, K., Lee, B., Sung, A.Y., et al. Treatment of childhood-onset restless legs syndrome and periodic limb movement disorder using intravenous iron sucrose. Sleep Med 14:11 (2013), 1100–1104.
16. [16] Ondo, W.G., Intravenous iron dextran for severe refractory restless legs syndrome. Sleep Med 11:5 (2010), 494–496.
17. [17] Grote, L., Leissner, L.L., Hedner, J., et al. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord 24:10 (2009), 1445–1452.
18. [18] Unger, E.L., Bianco, L.E., Jones, B., et al. Low brain iron effects and reversibility on striatal dopamine dynamics. Exp Neurol 261 (2014), 462–468.
19. [19] Allen, R.P., Connor, J.R., Hyland, K., et al. Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis. Sleep Med 10:1 (2009), 123–128.
20. [20] Connor, J.R., Wang, X.S., Allen, R.P., et al. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain 132:Pt 9 (2009), 2403–2412.
21. [21] Earley, C.J., Connor, J.R., Garcia-Borreguero, D., et al. Altered brain iron homeostasis and dopaminergic function in restless legs syndrome (Willis-Ekbom Disease). Sleep Med 15:11 (2014), 1288–1301.
22. [22] Earley, C.J., Kuwabara, H., Wong, D.F., et al. Increased synaptic dopamine in the putamen in restless legs syndrome. Sleep 36:1 (2013), 51–57.
23. [23] Connor, J.R., Boyer, P.J., Menzies, S.L., et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 61:3 (2003), 304–309.
24. [24] Allen, R.P., Barker, P.B., Wehrl, F.W., et al. MRI measurement of brain iron in patients with restless legs syndrome. Neurology 56:2 (2001), 263–265.
25. [25] Chang, Y., Paik, J.S., Lee, H.J., et al. Altered white matter integrity in primary restless legs syndrome patients: diffusion tensor imaging study. Neurol Res 36:8 (2014), 769–774.
26. [26] Sieminski, M., Losy, J., Partinen, M., Restless legs syndrome in multiple sclerosis. Sleep Med Rev 22 (2015), 15–22.
27. [27] Geguchadze, R.N., Coe, C.L., Lubach, G.R., et al. CSF proteomic analysis reveals persistent iron deficiency-induced alterations in non-human primate infants. J Neurochem 105:1 (2008), 127–136.
28. [28] Earley, C.J., Ponnuru, P., Wang, X., et al. Altered iron metabolism in lymphocytes from subjects with restless legs syndrome. Sleep 31:6 (2008), 847–852.
29. [29] Frauscher, B., Loscher, W., Hogl, B., et al. Auditory startle reaction is disinhibited in idiopathic restless legs syndrome. Sleep 30:4 (2007), 489–493.
30. [30] Unger, E.L., Bianco, L.E., Burhans, M.S., et al. Acoustic startle response is disrupted in iron-deficient rats. Pharmacol Biochem Behav 84:2 (2006), 378–384.
31. [31] Simpson, I.A., Ponnuru, P., Klinger, M.E., et al. A novel model for brain iron uptake: introducing the concept of regulation. J Cereb Blood Flow Metab 35:1 (2015), 48–57.
32. [32] Burdo, J.R., Simpson, I.A., Menzies, S., et al. Regulation of the profile of iron-management proteins in brain microvasculature. J Cereb Blood Flow Metab 24:1 (2004), 67–74.
33. [33] Burdo, J.R., Antonetti, D.A., Wolpert, E.B., et al. Mechanisms and regulation of transferrin and iron transport in a model blood-brain barrier system. Neuroscience 121:4 (2003), 883–890.
34. [34] Patton, S.M., Cho, Y.W., Clardy, T.W., et al. Proteomic analysis of the cerebrospinal fluid of patients with restless legs syndrome/Willis-Ekbom disease. Fluids Barriers CNS, 10(1), 2013, 20.
35. [35] Connor, J.R., Ponnuru, P., Wang, X.S., et al. Profile of altered brain iron acquisition in restless legs syndrome. Brain 134:Pt 4 (2011), 959–968.
36. [36] Snyder, A.M., Wang, X., Patton, S.M., et al. Mitochondrial ferritin in the substantia nigra in restless legs syndrome. J Neuropathol Exp Neurol 68:11 (2009), 1193–1199.
37. [37] Corsi, B., Cozzi, A., Arosio, P., et al. Human mitochondrial ferritin expressed in HeLa cells incorporates iron and affects cellular iron metabolism. J Biol Chem 277:25 (2002), 22430–22437.
38. [38] Gutsaeva, D.R., Carraway, M.S., Suliman, H.B., et al. Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism. J Neurosci 28:9 (2008), 2015–2024.
39. [39] Patton, S.M., Ponnuru, P., Snyder, A.M., et al. Hypoxia-inducible factor pathway activation in restless legs syndrome patients. Eur J Neurol 18:11 (2011), 1329–1335.
40. [40] De Ponti, C., Carini, R., Alchera, E., et al. Adenosine A2a receptor-mediated, normoxic induction of HIF-1 through PKC and PI-3K-dependent pathways in macrophages. J Leukoc Biol 82:2 (2007), 392–402.
41. [41] Kaelin, W.G. Jr., Ratcliffe, P.J., Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30:4 (2008), 393–402.
42. [42] Winkelmann, J., Lichtner, P., Putz, B., et al. Evidence for further genetic locus heterogeneity and confirmation of RLS-1 in restless legs syndrome. Mov Disord 21:1 (2006), 28–33.
43. [43] Jimenez-Jimenez, F.J., Alonso-Navarro, H., Martinez, C., et al. Neuronal nitric oxide synthase (nNOS, NOS1) rs693534 and rs7977109 variants and risk for restless legs syndrome. J Neural Transm (Vienna) 122:6 (2015), 819–823.
44. [44] Oskarsson, E., Wahlin-Larsson, B., Ulfberg, J., Reduced daytime intramuscular blood flow in patients with restless legs syndrome/Willis-Ekbom disease. Psychiatry Clin Neurosci 68:8 (2014), 640–643.
45. [45] Anderson, K.N., Di Maria, C., Allen, J., Novel assessment of microvascular changes in idiopathic restless legs syndrome (Willis-Ekbom disease). J Sleep Res 22:3 (2013), 315–321.
46. [46] Gulyani, S., Earley, C.J., Camandola, S., et al. Diminished iron concentrations increase adenosine A(2A) receptor levels in mouse striatum and cultured human neuroblastoma cells. Exp Neurol 215:2 (2009), 236–242.
47. [47] Wahlin-Larsson, B., Ulfberg, J., Aulin, K.P., et al. The expression of vascular endothelial growth factor in skeletal muscle of patients with sleep disorders. Muscle Nerve 40:4 (2009), 556–561.
48. [48] Bauser-Heaton, H.D., Bohlen, H.G., Cerebral microvascular dilation during hypotension and decreased oxygen tension: a role for nNOS. Am J Physiol Heart Circ Physiol 293:4 (2007), H2193–H21201.
49. [49] Volz, T.J., Schenk, J.O., L-arginine increases dopamine transporter activity in rat striatum via a nitric oxide synthase-dependent mechanism. Synapse 54:3 (2004), 173–182.
50. [50] Jordan, W., Hagedohm, J., Wiltfang, J., et al. Biochemical markers of cerebrovascular injury in sleep apnoea syndrome. Eur Respir J 20:1 (2002), 158–164.
51. [51] Ahmad, Y., Sharma, N.K., Garg, I., et al. An insight into the changes in human plasma proteome on adaptation to hypobaric hypoxia. PLoS One, 8(7), 2013, e67548.
52. [52] Wang, Z., Wu, D., Vinters, H.V., Hypoxia and reoxygenation of brain microvascular smooth muscle cells in vitro: cellular responses and expression of cerebral amyloid angiopathy-associated proteins. Apmis 110:5 (2002), 423–434.
53. [53] Gou, X., Wang, Z., Li, N., et al. Whole-genome sequencing of six dog breeds from continuous altitudes reveals adaptation to high-altitude hypoxia. Genome Res 24:8 (2014), 1308–1315.
54. [54] Connor, J.R., Wang, X.S., Patton, S.M., et al. Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology 62:9 (2004), 1563–1567.
55. [55] Cheng, C.M., Wang, D., Cao, X., et al. Iron regulatory protein 1 suppresses hypoxia-induced iron uptake proteins expression and decreases iron levels in HepG2 cells. J Cell Biochem 116:9 (2015), 1919–1931.
56. [56] Domachowske, J.B., Rafferty, S.P., Singhania, N., et al. Nitric oxide alters the expression of gamma-globin, H-ferritin, and transferrin receptor in human K562 cells at the posttranscriptional level. Blood 88:8 (1996), 2980–2988.
57. [57] Pantopoulos, K., Hentze, M.W., Nitric oxide signaling to iron-regulatory protein: direct control of ferritin mRNA translation and transferrin receptor mRNA stability in transfected fibroblasts. Proc Natl Acad Sci U. S. A 92:5 (1995), 1267–1271.
58. [58] Yoshioka, Y., Kosaka, N., Ochiya, T., et al. Micromanaging Iron Homeostasis: hypoxia-inducible micro-RNA-210 suppresses iron homeostasis-related proteins. J Biol Chem 287:41 (2012), 34110–34119.
59. [59] Sevim, S., Dogu, O., Camdeviren, H., et al. Unexpectedly low prevalence and unusual characteristics of RLS in Mersin, Turkey. Neurology 61:11 (2003), 1562–1569.
60. [60] Castillo, P.R., Kaplan, J., Lin, S.C., et al. Prevalence of restless legs syndrome among native South Americans residing in coastal and mountainous areas. Mayo Clin Proc 81:10 (2006), 1345–1347.
61. [61] Lo Coco, D., Mattaliano, A., Lo Coco, A., et al. Increased frequency of restless legs syndrome in chronic obstructive pulmonary disease patients. Sleep Med 10:5 (2009), 572–576.
62. [62] Kapsimalis, F., Kryger, M., Sleep breathing disorders in the U.S. female population. J Womens Health (Larchmt) 18:8 (2009), 1211–1219.
63. [63] Larsson, B.W., Kadi, F., Ulfberg, J., et al. Skeletal muscle morphology in patients with restless legs syndrome. Eur Neurol 58:3 (2007), 133–137.
64. [64] Salminen, A.V., Rimpila, V., Polo, O., Peripheral hypoxia in restless legs syndrome (Willis-Ekbom disease). Neurology 82:21 (2014), 1856–1861.
65. [65] Silva, B., Faustino, P., An overview of molecular basis of iron metabolism regulation and the associated pathologies. Biochim Biophys Acta 1852:7 (2015), 1347–1359.
66. [66] Benyamin, B., Esko, T., Ried, J.S., et al. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis. Nat Commun, 5, 2014, 4926.
67. [67] Ayton, S., Faux, N.G., Bush, A.I., Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE. Nat Commun, 6, 2015, 6760.
68. [68] Devireddy, L.R., Hart, D.O., Goetz, D.H., et al. A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell 141:6 (2010), 1006–1017.
69. [69] Ananth, S., Gnana-Prakasam, J.P., Bhutia, Y.D., et al. Regulation of the cholesterol efflux transporters ABCA1 and ABCG1 in retina in hemochromatosis and by the endogenous siderophore 2,5-dihydroxybenzoic acid. Biochim Biophys Acta 1842:4 (2014), 603–612.
70. [70] Karuppagounder, S.S., Kumar, A., Shao, D.S., et al. Metabolism and epigenetics in the nervous system: creating cellular fitness and resistance to neuronal death in neurological conditions via modulation of oxygen-, iron-, and 2-oxoglutarate-dependent dioxygenases. Brain Res 1628:Pt B (2015), 273–287.
71. [71] Hancock, R.L., Dunne, K., Walport, L.J., et al. Epigenetic regulation by histone demethylases in hypoxia. Epigenomics 7:5 (2015), 791–811.
72. [72] Lane, D.J., Richardson, D.R., Chaperone turns gatekeeper: PCBP2 and DMT1 form an iron- transport pipeline. Biochem J 462:1 (2014), e1–e3.
73. [73] Oexle, K., Schormair, B., Reid, J.S., et al. Dilution of candidates: the case of iron-related genes in restless legs syndrome. Eur J Hum Genet 21:4 (2013), 410–414.
74. [74] Constantine, C.C., Gurrin, L.C., McLaren, C.E., et al. SNP selection for genes of iron metabolism in a study of genetic modifiers of hemochromatosis. BMC Med Genet, 9, 2008, 18.
75. [75] Oexle, K., Ried, J.S., Hicks, A.A., et al. Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels. Hum Mol Genet 20:5 (2011), 1042–1047.
76. [76] Catoire, H., Dion, P.A., Xiong, L., et al. Restless legs syndrome-associated MEIS1 risk variant influences iron homeostasis. Ann Neurol 70:1 (2011), 170–175.
77. [77] Stefansson, H., Rye, D.B., Hicks, A., et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 357:7 (2007), 639–647.
78. [78] Sorensen, E., Grau, K., Berg, T., et al. A genetic risk factor for low serum ferritin levels in Danish blood donors. Transfusion 52:12 (2012), 2585–2589.
79. [79] DeAndrade, M.P., Johnson, R.L. Jr., Unger, E.L., et al. Motor restlessness, sleep disturbances, thermal sensory alterations and elevated serum iron levels in Btbd9 mutant mice. Hum Mol Genet 21:18 (2012), 3984–3992.
80. [80] Richards, K.C., Bost, J.E., Rogers, V.E., et al. Diagnostic accuracy of behavioral, activity, ferritin, and clinical indicators of restless legs syndrome. Sleep 38:3 (2015), 371–380.
81. [81] Beutler, E., Felitti, V., Gelbart, T., et al. Haematological effects of the C282Y HFE mutation in homozygous and heterozygous states among subjects of northern and southern European ancestry. Br J Haematol 120:5 (2003), 887–893.
82. [82] Barton, J.C., Wooten, V.D., Acton, R.T., Hemochromatosis and iron therapy of restless legs syndrome. Sleep Med 2:3 (2001), 249–251.
83. [83] Shaughnessy, P., Lee, J., O'Keeffe, S.T., Restless legs syndrome in patients with hereditary hemochromatosis. Neurology, 64(12), 2005, 2158.
84. [84] Haba-Rubio, J., Staner, L., Petiau, C., et al. Restless legs syndrome and low brain iron levels in patients with haemochromatosis. J Neurol Neurosurg Psychiatry 76:7 (2005), 1009–1010.
85. [85] Pollard, P.J., Loenarz, C., Mole, D.R., et al. Regulation of Jumonji-domain-containing histone demethylases by hypoxia- inducible factor (HIF)-1alpha. Biochem J 416:3 (2008), 387–394.
86. [86] Wellmann, S., Bettkober, M., Zelmer, A., et al. Hypoxia upregulates the histone demethylase JMJD1A via HIF-1. Biochem Biophys Res Commun 372:4 (2008), 892–897.
87. [87] Xia, X., Lemieux, M.E., Li, W., et al. Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc Natl Acad Sci U. S. A 106:11 (2009), 4260–4265.
88. [88] Lee, H.Y., Choi, K., Oh, H., et al. HIF-1-dependent induction of Jumonji domain-containing protein (JMJD) 3 under hypoxic conditions. Mol Cells 37:1 (2014), 43–50.
89. [89] Cascella, B., Mirica, L.M., Kinetic analysis of iron-dependent histone demethylases: alpha- ketoglutarate substrate inhibition and potential relevance to the regulation of histone demethylation in cancer cells. Biochemistry 51:44 (2012), 8699–8701.
90. [90] Sanchez-Fernandez, E.M., Tarhonskaya, H., Al-Qahtani, K., et al. Investigations on the oxygen dependence of a 2-oxoglutarate histone demethylase. Biochem J 449:2 (2013), 491–496.
91. 2 sensing. Science 292:5516 (2001), 464–468.
92. 2- regulated prolyl hydroxylation. Science 292:5516 (2001), 468–472.
93. [93] Metzen, E., Zhou, J., Jelkmann, W., et al. Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases. Mol Biol Cell 14:8 (2003), 3470–3481.
94. [94] Berchner-Pfannschmidt, U., Yamac, H., Trinidad, B., et al. Nitric oxide modulates oxygen sensing by hypoxia-inducible factor 1- dependent induction of prolyl hydroxylase 2. J Biol Chem 282:3 (2007), 1788–1796.
95. [95] Jepsen, K., Solum, D., Zhou, T., et al. SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature 450:7168 (2007), 415–419.
96. [96] Shahhoseini, M., Taghizadeh, Z., Hatami, M., et al. Retinoic acid dependent histone 3 demethylation of the clustered HOX genes during neural differentiation of human embryonic stem cells. Biochem Cell Biol 91:2 (2013), 116–122.
97. [97] Park, D.H., Hong, S.J., Salinas, R.D., et al. Activation of neuronal gene expression by the JMJD3 demethylase is required for postnatal and adult brain neurogenesis. Cell Rep 8:5 (2014), 1290–1299.
98. [98] He, X.B., Kim, M., Kim, S.Y., et al. Vitamin C facilitates dopamine neuron differentiation in fetal midbrain through TET1- and JMJD3-dependent epigenetic control manner. Stem Cells 33:4 (2015), 1320–1332.
99. [99] Bjornsson, H.T., Benjamin, J.S., Zhang, L., et al. Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome. Sci Transl Med, 6(256), 2014 p. 256ra135.
100. [100] Benjamin JS, Carosso GA, Pilarowski G, et al. The ketogenic diet rescues defects of hippocampal neurogenesis in a mouse model of Kabuki syndrome. 65th Annual Meeting of the American Society for Human Genetics, October 6–10, 2015 Baltimore, MD.
101. [101] Nandal, A., Ruiz, J.C., Subramanian, P., et al. Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2. Cell Metab 14:5 (2011), 647–657.
102. [102] Talarico, G., Canevelli, M., Tosto, G., et al. Restless legs syndrome in a group of patients with Alzheimer's disease. Am J Alzheimers Dis Other Demen 28:2 (2013), 165–170.
103. [103] Bliwise, D.L., Trotti, L.M., Yesavage, J.A., et al. Periodic leg movements in sleep in elderly patients with Parkinsonism and Alzheimer's disease. Eur J Neurol 19:6 (2012), 918–923.
104. [104] Lo Coco, D., Piccoli, F., La Bella, V., Restless legs syndrome in patients with amyotrophic lateral sclerosis. Mov Disord 25:15 (2010), 2658–2661.
105. [105] Limousin, N., Blasco, H., Corcia, P., et al. The high frequency of restless legs syndrome in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 12:4 (2011), 303–306.
106. [106] Ayton, S., Lei, P., Hare, D.J., et al. Parkinson's disease iron deposition caused by nitric oxide-induced loss of beta- amyloid precursor protein. J Neurosci 35:8 (2015), 3591–3597.
107. [107] Goodall, E.F., Haque, M.S., Morrison, K.E., Increased serum ferritin levels in amyotrophic lateral sclerosis (ALS) patients. J Neurol 255:11 (2008), 1652–1656.
108. [108] Su, X.W., Clardy, S.L., Stephens, H.E., et al. Serum ferritin is elevated in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Front Degener 16:1–2 (2015), 102–107.
109. [109] Couthouis, J., Hart, M.P., Erion, R., et al. Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum Mol Genet 21:13 (2012), 2899–2911.
110. [110] Kim, H.J., Kim, N.C., Wang, Y.D., et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:7442 (2013), 467–473.
111. [111] Goedert, M., NEURODEGENERATION. Alzheimer's and Parkinson's diseases: the prion concept in relation to assembled Abeta, tau, and alpha-synuclein. Science, 349(6248), 2015, 1255555.
112. [112] Jaunmuktane, Z., Mead, S., Ellis, M., et al. Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy. Nature 525:7568 (2015), 247–250.
113. [113] Patel, A., Lee, H.O., Jawerth, L., et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162:5 (2015), 1066–1077.
114. [114] Singh, A., Haldar, S., Horback, K., et al. Prion protein regulates iron transport by functioning as a ferrireductase. J Alzheimers Dis 35:3 (2013), 541–552.
115. [115] Singh, A., Kong, Q., Luo, X., et al. Prion protein (PrP) knock-out mice show altered iron metabolism: a functional role for PrP in iron uptake and transport. PLoS One, 4(7), 2009, e6115.
116. [116] Singh, N., The role of iron in prion disease and other neurodegenerative diseases. PLoS Pathog, 10(9), 2014, e1004335.
117. [117] McCarthy, R.C., Park, Y.H., Kosman, D.J., sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin. EMBO Rep 15:7 (2014), 809–815.
118. [118] Rogers, J.T., Randall, J.D., Cahill, C.M., et al. An iron-responsive element type II in the 5′-untranslated region of the Alzheimer's amyloid precursor protein transcript. J Biol Chem 277:47 (2002), 45518–45528.
119. [119] Cai, Z.X., Guo, H.S., Wang, C., et al. Double-edged roles of nitric oxide signaling on app processing and amyloid-beta production in vitro: preliminary evidence from sodium nitroprusside. Neurotox Res 29:1 (2016), 21–34.