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Iron Pathophysiology in Neurodegeneration with Brain Iron Accumulation

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Brain Iron Metabolism and CNS Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1173))

Abstract

Neurodegeneration with brain iron accumulation (NBIA) is a group of seriously devastating and life-threatening rare monogenic diseases characterized by focal iron accumulation in the brain. The main symptoms of NBIA comprise progressive movement disorder, often including painful dystonia, parkinsonism, mental disability, and early death. Currently, a single established therapy is not available to reverse the progression of these debilitating disorders. The complexity of NBIA emerged from the identification of various causative genes, and up to 15 genes have been identified to date. Although the NBIA genes are involved in different cellular biochemical pathways, they show the common characteristic of generating severe iron accumulation in the basal ganglia of the patients’ brains. Thus, the molecular events that lead to brain iron overload and their important roles in the pathophysiology of the diseases are not easy to identify and are poorly understood. This review summarizes the current knowledge on NBIA disorders, with a particular focus on the data describing the role of iron in the pathogenic mechanisms.

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References

  1. Akram M (2014) Citric acid cycle and role of its intermediates in metabolism. Cell Biochem Biophys 68:475–478

    Article  CAS  PubMed  Google Scholar 

  2. Alazami AM, Al-Saif A, Al-Semari A, Bohlega S, Zlitni S, Alzahrani F, Bavi P, Kaya N, Colak D, Khalak H, Baltus A, Peterlin B, Danda S, Bhatia KP, Schneider SA, Sakati N, Walsh CA, Al-Mohanna F, Meyer B, Alkuraya FS (2008) Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am J Hum Genet 83:684–691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Annesi G, Gagliardi M, Iannello G, Quattrone A (2016) Mutational analysis of COASY in an Italian patient with NBIA. Parkinsonism Relat Disord 28:150–151

    Article  PubMed  Google Scholar 

  4. Arber C, Angelova PR, Wiethoff S, Tsuchiya Y, Mazzacuva F, Preza E, Bhatia KP, Mills K, Gout I, Abramov AY, Hardy J, Duce JA, Houlden H, Wray S (2017) iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease. PLoS ONE 12:e0184104

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Baraibar MA, Barbeito AG, Muhoberac BB, Vidal R (2008) Iron-mediated aggregation and a localized structural change characterize ferritin from a mutant light chain polypeptide that causes neurodegeneration. J Biol Chem 283:31679–31689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Baraibar MA, Muhoberac BB, Garringer HJ, Hurley TD, Vidal R (2010) Unraveling of the E-helices and disruption of 4-fold pores are associated with iron mishandling in a mutant ferritin causing neurodegeneration. J Biol Chem 285:1950–1956

    Article  CAS  PubMed  Google Scholar 

  7. Barbeito AG, Garringer HJ, Baraibar MA, Gao X, Arredondo M, Nunez MT, Smith MA, Ghetti B, Vidal R (2009) Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene. J Neurochem 109:1067–1078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Barbeito AG, Levade T, Delisle MB, Ghetti B, Vidal R (2010) Abnormal iron metabolism in fibroblasts from a patient with the neurodegenerative disease hereditary ferritinopathy. Mol Neurodegener 5:50

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Beck G, Shinzawa K, Hayakawa H, Baba K, Yasuda T, Sumi-Akamaru H, Tsujimoto Y, Mochizuki H (2015) Deficiency of calcium-independent phospholipase A2 Beta induces brain iron accumulation through upregulation of divalent metal transporter 1. PLoS ONE 10:e0141629

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Beck G, Sugiura Y, Shinzawa K, Kato S, Setou M, Tsujimoto Y, Sakoda S, Sumi-Akamaru H (2011) Neuroaxonal dystrophy in calcium-independent phospholipase A2beta deficiency results from insufficient remodeling and degeneration of mitochondrial and presynaptic membranes. J Neurosci 31:11411–11420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Behrens MI, Bruggemann N, Chana P, Venegas P, Kagi M, Parrao T, Orellana P, Garrido C, Rojas CV, Hauke J, Hahnen E, Gonzalez R, Seleme N, Fernandez V, Schmidt A, Binkofski F, Kompf D, Kubisch C, Hagenah J, Klein C, Ramirez A (2010) Clinical spectrum of Kufor-Rakeb syndrome in the Chilean kindred with ATP13A2 mutations. Mov Disord 25:1929–1937

    Article  PubMed  Google Scholar 

  12. Berti CC, Dallabona C, Lazzaretti M, Dusi S, Tosi E, Tiranti V, Goffrini P (2015) Modeling human Coenzyme A synthase mutation in yeast reveals altered mitochondrial function, lipid content and iron metabolism. Microb Cell 2:126–135

    Article  CAS  Google Scholar 

  13. Bertoli-Avella AM, Garcia-Aznar JM, Brandau O, Al-Hakami F, Yuksel Z, Marais A, Gruning NM, Abbasi Moheb L, Paknia O, Alshaikh N, Alameer S, Marafi MJ, Al-Mulla F, Al-Sannaa N, Rolfs A, Bauer P (2018) Biallelic inactivating variants in the GTPBP2 gene cause a neurodevelopmental disorder with severe intellectual disability. Eur J Hum Genet 26:592–598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Brissot P, Ropert M, Le Lan C, Loreal O (2012) Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta 1820:403–410

    Article  CAS  PubMed  Google Scholar 

  15. Brunetti D, Dusi S, Giordano C, Lamperti C, Morbin M, Fugnanesi V, Marchet S, Fagiolari G, Sibon O, Moggio M, d’Amati G, Tiranti V (2014) Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model. Brain 137:57–68

    Article  PubMed  Google Scholar 

  16. Brunetti D, Dusi S, Morbin M, Uggetti A, Moda F, D’Amato I, Giordano C, d’Amati G, Cozzi A, Levi S, Hayflick S, Tiranti V (2012) Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model. Hum Mol Genet 21:5294–5305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Capoccia S, Maccarinelli F, Buffoli B, Rodella LF, Cremona O, Arosio P, Cirulli F (2015) Behavioral characterization of mouse models of neuroferritinopathy. PLoS ONE 10:e0118990

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Chinnery PF, Crompton DE, Birchall D, Jackson MJ, Coulthard A, Lombes A, Quinn N, Wills A, Fletcher N, Mottershead JP, Cooper P, Kellett M, Bates D, Burn J (2007) Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation. Brain 130:110–119

    Article  PubMed  Google Scholar 

  19. Cossu G, Abbruzzese G, Matta G, Murgia D, Melis M, Ricchi V, Galanello R, Barella S, Origa R, Balocco M, Pelosin E, Marchese R, Ruffinengo U, Forni GL (2014) Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): results from a four years follow-up. Parkinsonism Relat Disord 20:651–654

    Article  PubMed  Google Scholar 

  20. Cozzi A, Rovelli E, Frizzale G, Campanella A, Amendola M, Arosio P, Levi S (2010) Oxidative stress and cell death in cells expressing L-ferritin variants causing neuroferritinopathy. Neurobiol Dis 37:77–85

    Article  CAS  PubMed  Google Scholar 

  21. Cozzi A, Santambrogio P, Corsi B, Campanella A, Arosio P, Levi S (2006) Characterization of the l-ferritin variant 460InsA responsible of a hereditary ferritinopathy disorder. Neurobiol Dis 23:644–652

    Article  CAS  PubMed  Google Scholar 

  22. Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ, Jackson AP, McHale DP, Hay D, Barker WA, Markham AF, Bates D, Curtis A, Burn J (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28:350–354

    Article  CAS  PubMed  Google Scholar 

  23. de Figueiredo P, Doody A, Polizotto RS, Drecktrah D, Wood S, Banta M, Strang MS, Brown WJ (2001) Inhibition of transferrin recycling and endosome tubulation by phospholipase A2 antagonists. J Biol Chem 276:47361–47370

    Article  PubMed  Google Scholar 

  24. De Pace R, Skirzewski M, Damme M, Mattera R, Mercurio J, Foster AM, Cuitino L, Jarnik M, Hoffmann V, Morris HD, Han TU, Mancini GMS, Buonanno A, Bonifacino JS (2018) Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome. PLoS Genet 14:e1007363

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. de Tezanos Pinto F, Adamo HP (2018) The strategic function of the P5-ATPase ATP13A2 in toxic waste disposal. Neurochem Int 112:108–113

    Article  PubMed  CAS  Google Scholar 

  26. Devos D, Tchofo PJ, Vuillaume I, Destee A, Batey S, Burn J, Chinnery PF (2009) Clinical features and natural history of neuroferritinopathy caused by the 458dupA FTL mutation. Brain 132:e109

    Article  PubMed  Google Scholar 

  27. di Patti MC, Maio N, Rizzo G, De Francesco G, Persichini T, Colasanti M, Polticelli F, Musci G (2009) Dominant mutants of ceruloplasmin impair the copper loading machinery in aceruloplasminemia. J Biol Chem 284:4545–4554

    Article  PubMed  CAS  Google Scholar 

  28. Drecourt A, Babdor J, Dussiot M, Petit F, Goudin N, Garfa-Traore M, Habarou F, Bole-Feysot C, Nitschke P, Ottolenghi C, Metodiev MD, Serre V, Desguerre I, Boddaert N, Hermine O, Munnich A, Rotig A (2018) Impaired transferrin receptor palmitoylation and recycling in neurodegeneration with brain iron accumulation. Am J Hum Genet 102:266–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dusek P, Schneider SA (2012) Neurodegeneration with brain iron accumulation. Curr Opin Neurol 25:499–506

    Article  CAS  PubMed  Google Scholar 

  30. Dusek P, Schneider SA (2013) Neurodegenerative disorder with brain iron accumulation previously known as SENDA syndrome now genetically determined. Mov Disord 28:1051–1052

    Article  PubMed  Google Scholar 

  31. Dusi S, Valletta L, Haack TB, Tsuchiya Y, Venco P, Pasqualato S, Goffrini P, Tigano M, Demchenko N, Wieland T, Schwarzmayr T, Strom TM, Invernizzi F, Garavaglia B, Gregory A, Sanford L, Hamada J, Bettencourt C, Houlden H, Chiapparini L, Zorzi G, Kurian MA, Nardocci N, Prokisch H, Hayflick S, Gout I, Tiranti V (2014) Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. Am J Hum Genet 94:11–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Eiberg H, Hansen L, Korbo L, Nielsen IM, Svenstrup K, Bech S, Pinborg LH, Friberg L, Hjermind LE, Olsen OR, Nielsen JE (2012) Novel mutation in ATP13A2 widens the spectrum of Kufor-Rakeb syndrome (PARK9). Clin Genet 82:256–263

    Article  CAS  PubMed  Google Scholar 

  33. Evers C, Seitz A, Assmann B, Opladen T, Karch S, Hinderhofer K, Granzow M, Paramasivam N, Eils R, Diessl N, Bartram CR, Moog U (2017) Diagnosis of CoPAN by whole exome sequencing: waking up a sleeping tiger’s eye. Am J Med Genet A

    Google Scholar 

  34. Ferdinandusse S, Kostopoulos P, Denis S, Rusch H, Overmars H, Dillmann U, Reith W, Haas D, Wanders RJ, Duran M, Marziniak M (2006) Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy. Am J Hum Genet 78:1046–1052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Finkenstedt A, Wolf E, Hofner E, Gasser BI, Bosch S, Bakry R, Creus M, Kremser C, Schocke M, Theurl M, Moser P, Schranz M, Bonn G, Poewe W, Vogel W, Janecke AR, Zoller H (2010) Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation. J Hepatol 53:1101–1107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Garringer HJ, Irimia JM, Li W, Goodwin CB, Richine B, Acton A, Chan RJ, Peacock M, Muhoberac BB, Ghetti B, Vidal R (2016) Effect of systemic iron overload and a chelation therapy in a mouse model of the neurodegenerative disease hereditary Ferritinopathy. PLoS ONE 11:e0161341

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Gillis WQ, Kirmizitas A, Iwasaki Y, Ki DH, Wyrick JM, Thomsen GH (2016) Gtpbp2 is a positive regulator of Wnt signaling and maintains low levels of the Wnt negative regulator Axin. Cell Commun Signal 14:15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Gonzalez-Cuyar LF, Perry G, Miyajima H, Atwood CS, Riveros-Angel M, Lyons PF, Siedlak SL, Smith MA, Castellani RJ (2008) Redox active iron accumulation in aceruloplasminemia. Neuropathology 28:466–471

    Article  PubMed  Google Scholar 

  39. Gregory A, Hayflick SJ (2011) Genetics of neurodegeneration with brain iron accumulation. Curr Neurol Neurosci Rep 11:254–261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gregory A, Venkateswaran S, Hayflick SJ (2011) Fatty acid hydroxylase-associated neurodegeneration. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews((R)). Seattle, pp 1993–2018

    Google Scholar 

  41. Haack TB, Hogarth P, Kruer MC, Gregory A, Wieland T, Schwarzmayr T, Graf E, Sanford L, Meyer E, Kara E, Cuno SM, Harik SI, Dandu VH, Nardocci N, Zorzi G, Dunaway T, Tarnopolsky M, Skinner S, Frucht S, Hanspal E, Schrander-Stumpel C, Heron D, Mignot C, Garavaglia B, Bhatia K, Hardy J, Strom TM, Boddaert N, Houlden HH, Kurian MA, Meitinger T, Prokisch H, Hayflick SJ (2012) Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am J Hum Genet 91:1144–1149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hadziahmetovic M, Dentchev T, Song Y, Haddad N, He X, Hahn P, Pratico D, Wen R, Harris ZL, Lambris JD, Beard J, Dunaief JL (2008) Ceruloplasmin/hephaestin knockout mice model morphologic and molecular features of AMD. Invest Ophthalmol Vis Sci 49:2728–2736

    Article  PubMed  Google Scholar 

  43. Hadziahmetovic M, Song Y, Wolkow N, Iacovelli J, Grieco S, Lee J, Lyubarsky A, Pratico D, Connelly J, Spino M, Harris ZL, Dunaief JL (2011) The oral iron chelator deferiprone protects against iron overload-induced retinal degeneration. Invest Ophthalmol Vis Sci 52:959–968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hahn P, Qian Y, Dentchev T, Chen L, Beard J, Harris ZL, Dunaief JL (2004) Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Proc Natl Acad Sci U S A 101:13850–13855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Harris ZL, Durley AP, Man TK, Gitlin JD (1999) Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci U S A 96:10812–10817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E, Heim K, Roeber S, Tarabin V, Dusi S, Krajewska-Walasek M, Jozwiak S, Hempel M, Winkelmann J, Elstner M, Oexle K, Klopstock T, Mueller-Felber W, Gasser T, Trenkwalder C, Tiranti V, Kretzschmar H, Schmitz G, Strom TM, Meitinger T, Prokisch H (2011) Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Am J Hum Genet 89:543–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hayflick SJ, Kurian MA, Hogarth P (2018) Neurodegeneration with brain iron accumulation. Handb Clin Neurol 147:293–305

    Article  PubMed  PubMed Central  Google Scholar 

  48. Hellman NE, Kono S, Mancini GM, Hoogeboom AJ, De Jong GJ, Gitlin JD (2002) Mechanisms of copper incorporation into human ceruloplasmin. J Biol Chem 277:46632–46638

    Article  CAS  PubMed  Google Scholar 

  49. Hogarth P, Gregory A, Kruer MC, Sanford L, Wagoner W, Natowicz MR, Egel RT, Subramony SH, Goldman JG, Berry-Kravis E, Foulds NC, Hammans SR, Desguerre I, Rodriguez D, Wilson C, Diedrich A, Green S, Tran H, Reese L, Woltjer RL, Hayflick SJ (2013) New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. Neurology 80:268–275

    Article  PubMed  PubMed Central  Google Scholar 

  50. Horvath R, Holinski-Feder E, Neeve VC, Pyle A, Griffin H, Ashok D, Foley C, Hudson G, Rautenstrauss B, Nurnberg G, Nurnberg P, Kortler J, Neitzel B, Bassmann I, Rahman T, Keavney B, Loughlin J, Hambleton S, Schoser B, Lochmuller H, Santibanez-Koref M, Chinnery PF (2012) A new phenotype of brain iron accumulation with dystonia, optic atrophy, and peripheral neuropathy. Mov Disord 27:789–793

    Article  CAS  PubMed  Google Scholar 

  51. Horvath R, Lewis-Smith D, Douroudis K, Duff J, Keogh M, Pyle A, Fletcher N, Chinnery PF (2015) SCP2 mutations and neurodegeneration with brain iron accumulation. Neurology 85:1909–1911

    Article  PubMed  PubMed Central  Google Scholar 

  52. Ingrassia R, Memo M, Garavaglia B (2017) Ferrous iron up-regulation in fibroblasts of patients with beta propeller protein-associated neurodegeneration (BPAN). Front Genet 8:18

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Iuso A, Sibon OC, Gorza M, Heim K, Organisti C, Meitinger T, Prokisch H (2014) Impairment of Drosophila orthologs of the human orphan protein C19orf12 induces bang sensitivity and neurodegeneration. PLoS ONE 9:e89439

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Jaberi E, Rohani M, Shahidi GA, Nafissi S, Arefian E, Soleimani M, Rasooli P, Ahmadieh H, Daftarian N, KaramiNejadRanjbar M, Klotzle B, Fan JB, Turk C, Steemers F, Elahi E (2016) Identification of mutation in GTPBP2 in patients of a family with neurodegeneration accompanied by iron deposition in the brain. Neurobiol Aging 38:216 e211–216 e218

    Article  PubMed  CAS  Google Scholar 

  55. 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

    Article  CAS  PubMed  Google Scholar 

  56. Kaneko K, Hineno A, Yoshida K, Ohara S, Morita H, Ikeda S (2012) Extensive brain pathology in a patient with aceruloplasminemia with a prolonged duration of illness. Hum Pathol 43:451–456

    Article  PubMed  Google Scholar 

  57. Khatri D, Zizioli D, Tiso N, Facchinello N, Vezzoli S, Gianoncelli A, Memo M, Monti E, Borsani G, Finazzi D (2016) Down-regulation of coasy, the gene associated with NBIA-VI, reduces Bmp signaling, perturbs dorso-ventral patterning and alters neuronal development in zebrafish. Sci Rep 6:37660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kinghorn KJ, Castillo-Quan JI, Bartolome F, Angelova PR, Li L, Pope S, Cocheme HM, Khan S, Asghari S, Bhatia KP, Hardy J, Abramov AY, Partridge L (2015) Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction. Brain 138:1801–1816

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kono S (2012) Aceruloplasminemia. Curr Drug Targets 13:1190–1199

    Article  CAS  PubMed  Google Scholar 

  60. Kono S (2013) Aceruloplasminemia: an update. Int Rev Neurobiol 110:125–151

    Article  CAS  PubMed  Google Scholar 

  61. Kono S, Miyajima H (2006) Molecular and pathological basis of aceruloplasminemia. Biol Res 39:15–23

    Article  CAS  PubMed  Google Scholar 

  62. Kono S, Suzuki H, Oda T, Shirakawa K, Takahashi Y, Kitagawa M, Miyajima H (2007) Cys-881 is essential for the trafficking and secretion of truncated mutant ceruloplasmin in aceruloplasminemia. J Hepatol 47:844–850

    Article  CAS  PubMed  Google Scholar 

  63. Kono S, Yoshida K, Tomosugi N, Terada T, Hamaya Y, Kanaoka S, Miyajima H (2010) Biological effects of mutant ceruloplasmin on hepcidin-mediated internalization of ferroportin. Biochim Biophys Acta 1802:968–975

    Article  CAS  PubMed  Google Scholar 

  64. Kruer MC, Hiken M, Gregory A, Malandrini A, Clark D, Hogarth P, Grafe M, Hayflick SJ, Woltjer RL (2011) Novel histopathologic findings in molecularly-confirmed pantothenate kinase-associated neurodegeneration. Brain 134:947–958

    Article  PubMed  PubMed Central  Google Scholar 

  65. Kruer MC, Paisan-Ruiz C, Boddaert N, Yoon MY, Hama H, Gregory A, Malandrini A, Woltjer RL, Munnich A, Gobin S, Polster BJ, Palmeri S, Edvardson S, Hardy J, Houlden H, Hayflick SJ (2010) Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol 68:611–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kubota A, Hida A, Ichikawa Y, Momose Y, Goto J, Igeta Y, Hashida H, Yoshida K, Ikeda S, Kanazawa I, Tsuji S (2009) A novel ferritin light chain gene mutation in a Japanese family with neuroferritinopathy: description of clinical features and implications for genotype-phenotype correlations. Mov Disord 24:441–445

    Article  PubMed  Google Scholar 

  67. Kuo YM, Duncan JL, Westaway SK, Yang H, Nune G, Xu EY, Hayflick SJ, Gitschier J (2005) Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia. Hum Mol Genet 14:49–57

    Article  CAS  PubMed  Google Scholar 

  68. Kurian MA, Hayflick SJ (2013) Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN): review of two major neurodegeneration with brain iron accumulation (NBIA) phenotypes. Int Rev Neurobiol 110:49–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kurz T, Eaton JW, Brunk UT (2011) The role of lysosomes in iron metabolism and recycling. Int J Biochem Cell Biol 43:1686–1697

    Article  CAS  PubMed  Google Scholar 

  70. Langwinska-Wosko E, Skowronska M, Kmiec T, Czlonkowska A (2016) Retinal and optic nerve abnormalities in neurodegeneration associated with mutations in C19orf12 (MPAN). J Neurol Sci 370:237–240

    Article  CAS  PubMed  Google Scholar 

  71. Levi S, Finazzi D (2014) Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms. Front Pharmacol 5:99

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Levi S, Rovida E (2015) Neuroferritinopathy: from ferritin structure modification to pathogenetic mechanism. Neurobiol Dis 81:134–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Maccarinelli F, Pagani A, Cozzi A, Codazzi F, Di Giacomo G, Capoccia S, Rapino S, Finazzi D, Politi LS, Cirulli F, Giorgio M, Cremona O, Grohovaz F, Levi S (2015) A novel neuroferritinopathy mouse model (FTL 498InsTC) shows progressive brain iron dysregulation, morphological signs of early neurodegeneration and motor coordination deficits. Neurobiol Dis 81:119–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Maciel P, Cruz VT, Constante M, Iniesta I, Costa MC, Gallati S, Sousa N, Sequeiros J, Coutinho P, Santos MM (2005) Neuroferritinopathy: missense mutation in FTL causing early-onset bilateral pallidal involvement. Neurology 65:603–605

    Article  CAS  PubMed  Google Scholar 

  75. Malik I, Turk J, Mancuso DJ, Montier L, Wohltmann M, Wozniak DF, Schmidt RE, Gross RW, Kotzbauer PT (2008) Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations. Am J Pathol 172:406–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mancuso M, Davidzon G, Kurlan RM, Tawil R, Bonilla E, Di Mauro S, Powers JM (2005) Hereditary ferritinopathy: a novel mutation, its cellular pathology, and pathogenetic insights. J Neuropathol Exp Neurol 64:280–294

    Article  CAS  PubMed  Google Scholar 

  77. Mari F, Berti B, Romano A, Baldacci J, Rizzi R, Grazia Alessandri M, Tessa A, Procopio E, Rubegni A, Lourenco CM, Simonati A, Guerrini R, Santorelli FM (2018) Clinical and neuroimaging features of autosomal recessive spastic paraplegia 35 (SPG35): case reports, new mutations, and brief literature review. Neurogenetics 19:123–130

    Article  PubMed  Google Scholar 

  78. McNeill A, Birchall D, Hayflick SJ, Gregory A, Schenk JF, Zimmerman EA, Shang H, Miyajima H, Chinnery PF (2008) T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology 70:1614–1619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. McNeill A, Chinnery PF (2011) Neurodegeneration with brain iron accumulation. Handb Clin Neurol 100:161–172

    Article  PubMed  Google Scholar 

  80. Miyajima H (2003) Aceruloplasminemia, an iron metabolic disorder. Neuropathology 23:345–350

    Article  PubMed  Google Scholar 

  81. Miyajima H (2015) Aceruloplasminemia. Neuropathology 35:83–90

    Article  CAS  PubMed  Google Scholar 

  82. Miyajima H, Nishimura Y, Mizoguchi K, Sakamoto M, Shimizu T, Honda N (1987) Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration. Neurology 37:761–767

    Article  CAS  PubMed  Google Scholar 

  83. Moutton S, Fergelot P, Trocello JM, Plante-Bordeneuve V, Houcinat N, Wenisch E, Larue V, Brugieres P, Clot F, Lacombe D, Arveiler B, Goizet C (2014) A novel FTL mutation responsible for neuroferritinopathy with asymmetric clinical features and brain anomalies. Parkinsonism Relat Disord 20:935–937

    Article  PubMed  Google Scholar 

  84. Nishida K, Garringer HJ, Futamura N, Funakawa I, Jinnai K, Vidal R, Takao M (2014) A novel ferritin light chain mutation in neuroferritinopathy with an atypical presentation. J Neurol Sci 342:173–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ogimoto M, Anzai K, Takenoshita H, Kogawa K, Akehi Y, Yoshida R, Nakano M, Yoshida K, Ono J (2011) Criteria for early identification of aceruloplasminemia. Intern Med 50:1415–1418

    Article  PubMed  Google Scholar 

  86. Ohta E, Nagasaka T, Shindo K, Toma S, Nagasaka K, Ohta K, Shiozawa Z (2008) Neuroferritinopathy in a Japanese family with a duplication in the ferritin light chain gene. Neurology 70:1493–1494

    Article  CAS  PubMed  Google Scholar 

  87. Orellana DI, Santambrogio P, Rubio A, Yekhlef L, Cancellieri C, Dusi S, Giannelli SG, Venco P, Mazzara PG, Cozzi A, Ferrari M, Garavaglia B, Taverna S, Tiranti V, Broccoli V, Levi S (2016) Coenzyme A corrects pathological defects in human neurons of PANK2-associated neurodegeneration. EMBO Mol Med 8:1197–1211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Panteghini C, Zorzi G, Venco P, Dusi S, Reale C, Brunetti D, Chiapparini L, Zibordi F, Siegel B, Garavaglia B, Simonati A, Bertini E, Nardocci N, Tiranti V (2012) C19orf12 and FA2H mutations are rare in Italian patients with neurodegeneration with brain iron accumulation. Semin Pediatr Neurol 19:75–81

    Article  PubMed  Google Scholar 

  89. Patel BN, Dunn RJ, Jeong SY, Zhu Q, Julien JP, David S (2002) Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury. J Neurosci 22:6578–6586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Potter KA, Kern MJ, Fullbright G, Bielawski J, Scherer SS, Yum SW, Li JJ, Cheng H, Han X, Venkata JK, Khan PA, Rohrer B, Hama H (2011) Central nervous system dysfunction in a mouse model of FA2H deficiency. Glia 59:1009–1021

    Article  PubMed  PubMed Central  Google Scholar 

  91. Powers JM (2006) p53-mediated apoptosis, neuroglobin overexpression, and globin deposits in a patient with hereditary ferritinopathy. J Neuropathol Exp Neurol 65:716–721

    Article  CAS  PubMed  Google Scholar 

  92. Proikas-Cezanne T, Waddell S, Gaugel A, Frickey T, Lupas A, Nordheim A (2004) WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy. Oncogene 23:9314–9325

    Article  CAS  PubMed  Google Scholar 

  93. Rajagopalan S, Rane A, Chinta SJ, Andersen JK (2016) Regulation of ATP13A2 via PHD2-HIF1alpha signaling is critical for cellular iron homeostasis: implications for Parkinson’s disease. J Neurosci 36:1086–1095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP, Goebel I, Mubaidin AF, Wriekat AL, Roeper J, Al-Din A, Hillmer AM, Karsak M, Liss B, Woods CG, Behrens MI, Kubisch C (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38:1184–1191

    Article  CAS  PubMed  Google Scholar 

  95. Ramonet D, Podhajska A, Stafa K, Sonnay S, Trancikova A, Tsika E, Pletnikova O, Troncoso JC, Glauser L, Moore DJ (2012) PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity. Hum Mol Genet 21:1725–1743

    Article  CAS  PubMed  Google Scholar 

  96. Roberti Mdo R, Borges Filho HM, Goncalves CH, Lima FL (2011) Aceruloplasminemia: a rare disease—diagnosis and treatment of two cases. Rev Bras Hematol Hemoter 33:389–392

    Article  PubMed  Google Scholar 

  97. Roth AD, Nunez MT (2016) Oligodendrocytes: functioning in a delicate balance between high metabolic requirements and oxidative damage. Adv Exp Med Biol 949:167–181

    Article  CAS  PubMed  Google Scholar 

  98. Roubertie A, Hieu N, Roux CJ, Leboucq N, Manes G, Charif M, Echenne B, Goizet C, Guissart C, Meyer P, Marelli C, Rivier F, Burglen L, Horvath R, Hamel CP, Lenaers G (2018) AP4 deficiency: a novel form of neurodegeneration with brain iron accumulation? Neurol Genet 4:e217

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Salomao RP, Pedroso JL, Gama MT, Dutra LA, Maciel RH, Godeiro-Junior C, Chien HF, Teive HA, Cardoso F, Barsottini OG (2016) A diagnostic approach for neurodegeneration with brain iron accumulation: clinical features, genetics and brain imaging. Arq Neuropsiquiatr 74:587–596

    Article  PubMed  Google Scholar 

  100. Santambrogio P, Dusi S, Guaraldo M, Rotundo LI, Broccoli V, Garavaglia B, Tiranti V, Levi S (2015) Mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients. Neurobiol Dis 81:144–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Schneider SA, Bhatia KP (2012) Syndromes of neurodegeneration with brain iron accumulation. Semin Pediatr Neurol 19:57–66

    Article  PubMed  Google Scholar 

  102. Schultheis PJ, Fleming SM, Clippinger AK, Lewis J, Tsunemi T, Giasson B, Dickson DW, Mazzulli JR, Bardgett ME, Haik KL, Ekhator O, Chava AK, Howard J, Gannon M, Hoffman E, Chen Y, Prasad V, Linn SC, Tamargo RJ, Westbroek W, Sidransky E, Krainc D, Shull GE (2013) Atp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis, limited alpha-synuclein accumulation and age-dependent sensorimotor deficits. Hum Mol Genet 22:2067–2082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Schulz K, Vulpe CD, Harris LZ, David S (2011) Iron efflux from oligodendrocytes is differentially regulated in gray and white matter. J Neurosci 31:13301–13311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Seibler P, Burbulla LF, Dulovic M, Zittel S, Heine J, Schmidt T, Rudolph F, Westenberger A, Rakovic A, Munchau A, Krainc D, Klein C (2018) Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells. Brain 141:3052–3064

    Article  PubMed  PubMed Central  Google Scholar 

  105. Storti E, Cortese F, Di Fabio R, Fiorillo C, Pierallini A, Tessa A, Valleriani A, Pierelli F, Santorelli FM, Casali C (2013) De novo FTL mutation: a clinical, neuroimaging, and molecular study. Mov Disord 28:252–253

    Article  PubMed  Google Scholar 

  106. Texel SJ, Camandola S, Ladenheim B, Rothman SM, Mughal MR, Unger EL, Cadet JL, Mattson MP (2012) Ceruloplasmin deficiency results in an anxiety phenotype involving deficits in hippocampal iron, serotonin, and BDNF. J Neurochem 120:125–134

    Article  CAS  PubMed  Google Scholar 

  107. Venco P, Bonora M, Giorgi C, Papaleo E, Iuso A, Prokisch H, Pinton P, Tiranti V (2015) Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca(2)(+). Front Genet 6:185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Vidal R, Delisle MB, Rascol O, Ghetti B (2003) Hereditary ferritinopathy. J Neurol Sci 207:110–111

    Article  PubMed  Google Scholar 

  109. Vidal R, Ghetti B, Takao M, Brefel-Courbon C, Uro-Coste E, Glazier BS, Siani V, Benson MD, Calvas P, Miravalle L, Rascol O, Delisle MB (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

    Article  CAS  PubMed  Google Scholar 

  110. Vidal R, Miravalle L, Gao X, Barbeito AG, Baraibar MA, Hekmatyar SK, Widel M, Bansal N, Delisle MB, Ghetti B (2008) Expression of a mutant form of the ferritin light chain gene induces neurodegeneration and iron overload in transgenic mice. J Neurosci 28:60–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wanders RJ, Jansen GA, Lloyd MD (2003) Phytanic acid alpha-oxidation, new insights into an old problem: a review. Biochim Biophys Acta 1631:119–135

    Article  CAS  PubMed  Google Scholar 

  112. Yamamoto K, Yoshida K, Miyagoe Y, Ishikawa A, Hanaoka K, Nomoto S, Kaneko K, Ikeda S, Takeda S (2002) Quantitative evaluation of expression of iron-metabolism genes in ceruloplasmin-deficient mice. Biochim Biophys Acta 1588:195–202

    Article  CAS  PubMed  Google Scholar 

  113. Yang Y, Wu Z, Kuo YM, Zhou B (2005) Dietary rescue of fumble—a Drosophila model for pantothenate-kinase-associated neurodegeneration. J Inherit Metab Dis 28:1055–1064

    Article  CAS  PubMed  Google Scholar 

  114. Yoshida K, Furihata K, Takeda S, Nakamura A, Yamamoto K, Morita H, Hiyamuta S, Ikeda S, Shimizu N, Yanagisawa N (1995) A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat Genet 9:267–272

    Article  CAS  PubMed  Google Scholar 

  115. Zanardi A, Conti A, Cremonesi M, D’Adamo P, Gilberti E, Apostoli P, Cannistraci CV, Piperno A, David S, Alessio M (2018) Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia. EMBO Mol Med 10:91–106

    Article  CAS  PubMed  Google Scholar 

  116. Zhao Z, Zhang X, Zhao C, Choi J, Shi J, Song K, Turk J, Ma ZA (2010) Protection of pancreatic beta-cells by group VIA phospholipase A(2)-mediated repair of mitochondrial membrane peroxidation. Endocrinology 151:3038–3048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zinoviev A, Goyal A, Jindal S, LaCava J, Komar AA, Rodnina MV, Hellen CUT, Pestova TV (2018) Functions of unconventional mammalian translational GTPases GTPBP1 and GTPBP2. Genes Dev 32:1226–1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zizioli D, Tiso N, Guglielmi A, Saraceno C, Busolin G, Giuliani R, Khatri D, Monti E, Borsani G, Argenton F, Finazzi D (2016) Knock-down of pantothenate kinase 2 severely affects the development of the nervous and vascular system in zebrafish, providing new insights into PKAN disease. Neurobiol Dis 85:35–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Zorzi G, Zibordi F, Chiapparini L, Bertini E, Russo L, Piga A, Longo F, Garavaglia B, Aquino D, Savoiardo M, Solari A, Nardocci N (2011) Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial. Mov Disord 26:1756–1759

    Article  PubMed  Google Scholar 

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Acknowledgements

The financial support from Telethon-Italia (Grant nos. GGP10099, GGP11088 and GGP16234 to SL) and AISNAF (to SL) is gratefully acknowledged. The authors are grateful to Dr. Ermanna Rovida for assisting with the figure preparation.

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  1. Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy

    Sonia Levi

  2. Division of Neuroscience, San Raffaele Scientific Institute, 20132, Milan, Italy

    Anna Cozzi & Paolo Santambrogio

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  1. Sonia Levi
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  2. Anna Cozzi
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  3. Paolo Santambrogio
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Correspondence to Sonia Levi .

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  1. College of Life Sciences, Hebei Normal University , Shijiazhuang, Hebei, China

    Yan-Zhong Chang

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Levi, S., Cozzi, A., Santambrogio, P. (2019). Iron Pathophysiology in Neurodegeneration with Brain Iron Accumulation. In: Chang, YZ. (eds) Brain Iron Metabolism and CNS Diseases. Advances in Experimental Medicine and Biology, vol 1173. Springer, Singapore. https://doi.org/10.1007/978-981-13-9589-5_9

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