Precision medicine in pantothenate kinase-associated neurodegeneration
|
摘要
Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas,mainly the basal ganglia.The predominant clinical symptoms include spasticity,progressive dystonia,Parkinson's disease-like symptoms,neuropsychiatric alterations,and retinal degeneration.Among the neurodegeneration with brain iron accumulation disorders,the most frequent subtype is pantothenate kinase-associated neurodegeneration(PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2(PANK2)which catalyzed the first reaction of the coenzyme A biosynthesis pathway.Currently there is no effective treatment to prevent the inexorable course of these disorders.The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN.Recently,we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules,mitochondrial dysfunction and a pronounced increase of markers of oxidative stress.In addition,PKAN fibroblasts showed a morphological senescence-like phenotype.Interestingly,pantothenate supplementation,the substrate of the PANK2 enzyme,corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression.However,pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein.The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts.Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations.Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment.The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate.The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available,and monitoring its effect on the pathophysiological changes,can help for a better therapeutic strategy.In addition,these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future.
Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas,mainly the basal ganglia.The predominant clinical symptoms include spasticity,progressive dystonia,Parkinson's disease-like symptoms,neuropsychiatric alterations,and retinal degeneration.Among the neurodegeneration with brain iron accumulation disorders,the most frequent subtype is pantothenate kinase-associated neurodegeneration(PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2(PANK2)which catalyzed the first reaction of the coenzyme A biosynthesis pathway.Currently there is no effective treatment to prevent the inexorable course of these disorders.The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN.Recently,we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules,mitochondrial dysfunction and a pronounced increase of markers of oxidative stress.In addition,PKAN fibroblasts showed a morphological senescence-like phenotype.Interestingly,pantothenate supplementation,the substrate of the PANK2 enzyme,corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression.However,pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein.The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts.Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations.Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment.The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate.The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available,and monitoring its effect on the pathophysiological changes,can help for a better therapeutic strategy.In addition,these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future.
Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas,mainly the basal ganglia.The predominant clinical symptoms include spasticity,progressive dystonia,Parkinson's disease-like symptoms,neuropsychiatric alterations,and retinal degeneration.Among the neurodegeneration with brain iron accumulation disorders,the most frequent subtype is pantothenate kinase-associated neurodegeneration(PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2(PANK2)which catalyzed the first reaction of the coenzyme A biosynthesis pathway.Currently there is no effective treatment to prevent the inexorable course of these disorders.The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN.Recently,we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules,mitochondrial dysfunction and a pronounced increase of markers of oxidative stress.In addition,PKAN fibroblasts showed a morphological senescence-like phenotype.Interestingly,pantothenate supplementation,the substrate of the PANK2 enzyme,corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression.However,pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein.The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts.Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations.Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment.The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate.The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available,and monitoring its effect on the pathophysiological changes,can help for a better therapeutic strategy.In addition,these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future.
引文
Afshar K,Gonczy P,DiNardo S,Wasserman SA(2001)fumble encodes a pantothenate kinase homolog required for proper mitosis and meiosis in Drosophila melanogaster.Genetics 157:1267-1276.
álvarez-Córdoba M,Fernández Khoury A,Villanueva-Paz M,Gó-mez-Navarro C,Villalón-García I,Suárez-Rivero JM,Povea-Cabello S,de la Mata M,Cotán D,Talaverón-Rey M,Pérez-Pulido AJ,Salas JJ,Pérez-Villegas EM,Díaz-Quintana A,Armengol JA,Sánchez-Alcázar JA(2018)Pantothenate rescues iron accumulation in Pantothenate Kinase-associated neurodegeneration depending on the type of mutation.Mol Neurobiol doi:10.1007/s12035-018-1333-0.
Andreotti G,Guarracino MR,Cammisa M,Correra A,Cubellis MV(2010)Prediction of the responsiveness to pharmacological chaperones:lysosomal human alpha-galactosidase,a case of study.Orphanet J Rare Dis 5:36.
Andreotti G,Cabeza de Vaca I,Poziello A,Monti MC,Guallar V,Cubellis MV(2014)Conformational response to ligand binding in phosphomannomutase2:insights into inborn glycosylation disorder.J Biol Chem 289:34900-34910.
Bendikov-Bar I,Maor G,Filocamo M,Horowitz M(2013)Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase.Blood Cells Mol Dis 50:141-145.
Berman SB,Hastings TG(1999)Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria:implications for Parkinson’s disease.J Neurochem73:1127-1137.
Biosa A,Arduini I,Soriano ME,Giorgio V,Bernardi P,Bisaglia M,Bubacco L(2018)Dopamine oxidation products as mitochondrial endotoxins,a potential molecular mechanism for preferential neurodegeneration in Parkinson’s disease.ACS Chem Neurosci 9:2849-2858.
Bohic S,Murphy K,Paulus W,Cloetens P,Salome M,Susini J,Double K(2008)Intracellular chemical imaging of the developmental phases of human neuromelanin using synchrotron X-ray microspectroscopy.Anal Chem 80:9557-9566.
Bosveld F,Rana A,van der Wouden PE,Lemstra W,Ritsema M,Kampinga HH,Sibon OC(2008)De novo CoA biosynthesis is required to maintain DNA integrity during development of the Drosophila nervous system.Hum Mol Genet 17:2058-2069.
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 knockout mouse model.Hum Mol Genet 21:5294-5305.
Brunk UT,Terman A(2002)Lipofuscin:mechanisms of age-related accumulation and influence on cell function.Free Radic Biol Med33:611-619.
Campanella A,Privitera D,Guaraldo M,Rovelli E,Barzaghi C,Garavaglia B,Santambrogio P,Cozzi A,Levi S(2012)Skin fibroblasts from pantothenate kinase-associated neurodegeneration patients show altered cellular oxidative status and have defective iron-handling properties.Hum Mol Genet 21:4049-4059.
Colman A,Dreesen O(2009)Pluripotent stem cells and disease modeling.Cell Stem Cell 5:244-247.
Connolly GP(1998)Fibroblast models of neurological disorders:fluorescence measurement studies.Trends Pharmacol Sci 19:171-177.
Defendini R,Markesbery WR,Mastri AR,Duffy PE(1973)Hallervorden-Spatz disease and infantile neuroaxonal dystrophy.Ultrastructural observations,anatomical pathology and nosology.J Neurol Sci 20:7-23.
Di Meo I,Tiranti V(2018)Classification and molecular pathogenesis of NBIA syndromes.Eur J Paediatr Neurol 22:272-284.
Dolmetsch R,Geschwind DH(2011)The human brain in a dish:the promise of iPSC-derived neurons.Cell 145:831-834.
Double KL,Dedov VN,Fedorow H,Kettle E,Halliday GM,Garner B,Brunk UT(2008)The comparative biology of neuromelanin and lipofuscin in the human brain.Cell Mol Life Sci 65:1669-1682.
Drouin-Ouellet J,Lau S,Brattas PL,Rylander Ottosson D,Pircs K,Grassi DA,Collins LM,Vuono R,Andersson Sjoland A,Westergren-Thorsson G,Graff C,Minthon L,Toresson H,Barker RA,Jakobsson J,Parmar M(2017)REST suppression mediates neural conversion of adult human fibroblasts via microRNA-dependent and-independent pathways.EMBO Mol Med 9:1117-1131.
Frolova MS,Surin AM,Braslavski AV,Vekshin NL(2015)Degradation of mitochondria to lipofuscin upon heating and illumination.Biofizika 60:1125-1131.
Gerlach M,Riederer P,Double KL(2008)Neuromelanin-bound ferric iron as an experimental model of dopaminergic neurodegeneration in Parkinson’s disease.Parkinsonism Relat Disord 14 Suppl 2:S185-188.
Gerlach M,Double KL,Ben-Shachar D,Zecca L,Youdim MB,Riederer P(2003)Neuromelanin and its interaction with iron as a potential risk factor for dopaminergic neurodegeneration underlying Parkinson’s disease.Neurotox Res 5:35-44.
Goldin E,Zheng W,Motabar O,Southall N,Choi JH,Marugan J,Austin CP,Sidransky E(2012)High throughput screening for small molecule therapy for Gaucher disease using patient tissue as the source of mutant glucocerebrosidase.PLoS One 7:e29861.
Gregory A,Hayflick SJ(2005)Neurodegeneration with brain iron accumulation.Folia Neuropathol 43:286-296.
Gregory A,Polster BJ,Hayflick SJ(2009)Clinical and genetic delineation of neurodegeneration with brain iron accumulation.J Med Genet 46:73-80.
Hare DJ,Double KL(2016)Iron and dopamine:a toxic couple.Brain139:1026-1035.
Hay Mele B,Citro V,Andreotti G,Cubellis MV(2015)Drug repositioning can accelerate discovery of pharmacological chaperones.Orphanet J Rare Dis 10:55.
Hayflick SJ(2006)Neurodegeneration with brain iron accumulation:from genes to pathogenesis.Semin Pediatr Neurol 13:182-185.
Hayflick SJ,Westaway SK,Levinson B,Zhou B,Johnson MA,Ching KH,Gitschier J(2003)Genetic,clinical,and radiographic delineation of Hallervorden-Spatz syndrome.N Engl J Med 348:33-40.
H?hn A,Grune T(2013)Lipofuscin:formation,effects and role of macroautophagy.Redox Biol 1:140-144.
Horvath S(2013)DNA methylation age of human tissues and cell types.Genome Biol 14:R115.
Huang ML,Lane DJ,Richardson DR(2011)Mitochondrial mayhem:the mitochondrion as a modulator of iron metabolism and its role in disease.Antioxid Redox Signal 15:3003-3019.
Huh CJ,Zhang B,Victor MB,Dahiya S,Batista LF,Horvath S,Yoo AS(2016)Maintenance of age in human neurons generated by microR-NA-based neuronal conversion of fibroblasts.eLife 5:e18648.
Ishihara K,Okuyama S,Kumano S,Iida K,Hamana H,Murakoshi M,Kobayashi T,Usami S,Ikeda K,Haga Y,Tsumoto K,Nakamura H,Hirasawa N,Wada H(2010)Salicylate restores transport function and anion exchanger activity of missense pendrin mutations.Hear Res 270:110-118.
Johnson MA,Kuo YM,Westaway SK,Parker SM,Ching KH,Gitschier J,Hayflick SJ(2004)Mitochondrial localization of human PANK2and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration.Ann N Y Acad Sci 1012:282-298.
Jolly RD,Douglas BV,Davey PM,Roiri JE(1995)Lipofuscin in bovine muscle and brain:a model for studying age pigment.Gerontology 41Suppl 2:283-295.
Jung T,Bader N,Grune T(2007)Lipofuscin:formation,distribution,and metabolic consequences.Ann N Y Acad Sci 1119:97-111.
Karlsson O,Lindquist NG(2016)Melanin and neuromelanin binding of drugs and chemicals:toxicological implications.Arch Toxicol90:1883-1891.
Kim J,Basak JM,Holtzman DM(2009)The role of apolipoprotein E in Alzheimer’s disease.Neuron 63:287-303.
Koh HJ,Lee SM,Son BG,Lee SH,Ryoo ZY,Chang KT,Park JW,Park DC,Song BJ,Veech RL,Song H,Huh TL(2004)Cytosolic NAD-P+-dependent isocitrate dehydrogenase plays a key role in lipid metabolism.J Biol Chem 279:39968-39974.
Konig J,Ott C,Hugo M,Jung T,Bulteau AL,Grune T,Hohn A(2017)Mitochondrial contribution to lipofuscin formation.Redox Biol11:673-681.
Kruer MC(2013)The neuropathology of neurodegeneration with brain iron accumulation.Int Rev Neurobiol 110:165-194.
Kuo YM,Hayflick SJ,Gitschier J(2007)Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase-associated neurodegeneration.J Inherit Metab Dis 30:310-317.
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.
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.
Kurz T,Terman A,Gustafsson B,Brunk UT(2008)Lysosomes and oxidative stress in aging and apoptosis.Biochim Biophys Acta1780:1291-1303.
Ladewig J,Koch P,Brustle O(2013)Leveling Waddington:the emergence of direct programming and the loss of cell fate hierarchies.Nat Rev Mol Cell Biol 14:225-236.
Ladewig J,Mertens J,Kesavan J,Doerr J,Poppe D,Glaue F,Herms S,Wernet P,Kogler G,Muller FJ,Koch P,Brustle O(2012)Small molecules enable highly efficient neuronal conversion of human fibroblasts.Nat Methods 9:575-578.
Lan AP,Chen J,Chai ZF,Hu Y(2016)The neurotoxicity of iron,copper and cobalt in Parkinson’s disease through ROS-mediated mechanisms.Biometals 29:665-678.
Leonardi R,Zhang YM,Lykidis A,Rock CO,Jackowski S(2007)Localization and regulation of mouse pantothenate kinase 2.FEBS Lett581:4639-4644.
Levi S,Finazzi D(2014)Neurodegeneration with brain iron accumulation:update on pathogenic mechanisms.Front Pharmacol 5:99.
Lill R,Srinivasan V,Muhlenhoff U(2014)The role of mitochondria in cytosolic-nuclear iron-sulfur protein biogenesis and in cellular iron regulation.Curr Opin Microbiol 22:111-119.
Lu C,Cortopassi G(2007)Frataxin knockdown causes loss of cytoplasmic iron-sulfur cluster functions,redox alterations and induction of heme transcripts.Arch Biochem Biophys 457:111-122.
Luckenbach MW,Green WR,Miller NR,Moser HW,Clark AW,Tennekoon G(1983)Ocular clinicopathologic correlation of Hallervorden-Spatz syndrome with acanthocytosis and pigmentary retinopathy.Am J Ophthalmol 95:369-382.
Maegawa GH,Tropak M,Buttner J,Stockley T,Kok F,Clarke JT,Mahuran DJ(2007)Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis.J Biol Chem 282:9150-9161.
Maitra R,Hamilton JW(2007)Altered biogenesis of deltaF508-CFTR following treatment with doxorubicin.Cell Physiol Biochem 20:465-472.
Martin GM,Chen PC,Devaraneni P,Shyng SL(2013)Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels.Front Physiol 4:386.
Matsunaga T,Kotamraju S,Kalivendi SV,Dhanasekaran A,Joseph J,Kalyanaraman B(2004)Ceramide-induced intracellular oxidant formation,iron signaling,and apoptosis in endothelial cells:protective role of endogenous nitric oxide.J Biol Chem 279:28614-28624.
Mertens J,Paquola ACM,Ku M,Hatch E,Bohnke L,Ladjevardi S,McGrath S,Campbell B,Lee H,Herdy JR,Goncalves JT,Toda T,Kim Y,Winkler J,Yao J,Hetzer MW,Gage FH(2015)Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects.Cell Stem Cell 17:705-718.
Miura K,Okada Y,Aoi T,Okada A,Takahashi K,Okita K,Nakagawa M,Koyanagi M,Tanabe K,Ohnuki M,Ogawa D,Ikeda E,Okano H,Yamanaka S(2009)Variation in the safety of induced pluripotent stem cell lines.Nat Biotechnol 27:743-745.
Napolitano A,Crescenzi O,Pezzella A,Prota G(1995)Generation of the neurotoxin 6-hydroxydopamine by peroxidase/H2O2 oxidation of dopamine.J Med Chem 38:917-922.
Newton CL,Whay AM,McArdle CA,Zhang M,van Koppen CJ,van de Lagemaat R,Segaloff DL,Millar RP(2011)Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist.Proc Natl Acad Sci U S A 108:7172-7176.
Nunez MT,Urrutia P,Mena N,Aguirre P,Tapia V,Salazar J(2012)Iron toxicity in neurodegeneration.Biometals 25:761-776.
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.
Pang ZP,Yang N,Vierbuchen T,Ostermeier A,Fuentes DR,Yang TQ,Citri A,Sebastiano V,Marro S,Sudhof TC,Wernig M(2011)Induction of human neuronal cells by defined transcription factors.Nature 476:220-223.
Park BE,Netsky MG,Betsill WL,Jr.(1975)Pathogenesis of pigment and spheroid formation in Hallervorden-Spatz syndrome and related disorders.Neurology 25:1172-1178.
Perry TL,Norman MG,Yong VW,Whiting S,Crichton JU,Hansen S,Kish SJ(1985)Hallervorden-Spatz disease:cysteine accumulation and cysteine dioxygenase deficiency in the globus pallidus.Ann Neurol 18:482-489.
Pezzella A,d’Ischia M,Napolitano A,Misuraca G,Prota G(1997)Iron-mediated generation of the neurotoxin 6-hydroxydopamine quinone by reaction of fatty acid hydroperoxides with dopamine:a possible contributory mechanism for neuronal degeneration in Parkinson’s disease.J Med Chem 40:2211-2216.
Pfisterer U,Ek F,Lang S,Soneji S,Olsson R,Parmar M(2016)Small molecules increase direct neural conversion of human fibroblasts.Sci Rep 6:38290.
Poli M,Derosas M,Luscieti S,Cavadini P,Campanella A,Verardi R,Finazzi D,Arosio P(2010)Pantothenate kinase-2(Pank2)silencing causes cell growth reduction,cell-specific ferroportin upregulation and iron deregulation.Neurobiol Dis 39:204-210.
Porto C,Ferrara MC,Meli M,Acampora E,Avolio V,Rosa M,Cobucci-Ponzano B,Colombo G,Moracci M,Andria G,Parenti G(2012)Pharmacological enhancement of alpha-glucosidase by the allosteric chaperone N-acetylcysteine.Mol Ther 20:2201-2211.
Powell SR,Wang P,Divald A,Teichberg S,Haridas V,McCloskey TW,Davies KJ,Katzeff H(2005)Aggregates of oxidized proteins(lipofuscin)induce apoptosis through proteasome inhibition and dysregulation of proapoptotic proteins.Free Radic Biol Med 38:1093-1101.
Rana A,Seinen E,Siudeja K,Muntendam R,Srinivasan B,van der Want JJ,Hayflick S,Reijngoud DJ,Kayser O,Sibon OC(2010)Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration.Proc Natl Acad Sci U S A 107:6988-6993.
Reeg S,Grune T(2015)Protein oxidation in aging:does it play a role in aging progression?Antioxid Redox Signal 23:239-255.
Rigat B,Mahuran D(2009)Diltiazem,a L-type Ca(2+)channel blocker,also acts as a pharmacological chaperone in Gaucher patient cells.Mol Genet Metab 96:225-232.
Salvador GA,Uranga RM,Giusto NM(2010)Iron and mechanisms of neurotoxicity.Int J Alzheimers Dis 2011:720658.
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.
Schee Genannt Halfmann S,Mahlmann L,Leyens L,Reumann M,Brand A(2017)Personalized medicine:what’s in it for rare diseases?Adv Exp Med Biol 1031:387-404.
Strafella C,Caputo V,Galota MR,Zampatti S,Marella G,Mauriello S,Cascella R,Giardina E(2018)Application of precision medicine in neurodegenerative diseases.Front Neurol 9:701.
Sulzer D,Bogulavsky J,Larsen KE,Behr G,Karatekin E,Kleinman MH,Turro N,Krantz D,Edwards RH,Greene LA,Zecca L(2000)Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles.Proc Natl Acad Sci U SA 97:11869-11874.
Swaiman KF,Smith SA,Trock GL,Siddiqui AR(1983)Sea-blue histiocytes,lymphocytic cytosomes,movement disorder and 59Fe-uptake in basal ganglia:Hallervorden-Spatz disease or ceroid storage disease with abnormal isotope scan?Neurology 33:301-305.
Tan L,Jiang T,Tan L,Yu JT(2016)Toward precision medicine in neurological diseases.Ann Transl Med 4:104.
Tello C,Darling A,Lupo V,Perez-Duenas B,Espinos C(2018)On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation.Clin Genet 93:731-740.
Titova N,Chaudhuri KR(2017)Personalized medicine in Parkinson’s disease:Time to be precise.Mov Disord 32:1147-1154.
Tong WH,Rouault TA(2007)Metabolic regulation of citrate and iron by aconitases:role of iron-sulfur cluster biogenesis.Biometals20:549-564.
Torper O,Pfisterer U,Wolf DA,Pereira M,Lau S,Jakobsson J,Bj?rklund A,Grealish S,Parmar M(2013)Generation of induced neurons via direct conversion in vivo.Proc Natl Acad Sci U S A110:7038-7043.
Vierbuchen T,Ostermeier A,Pang ZP,Kokubu Y,Südhof TC,Wernig M(2010)Direct conversion of fibroblasts to functional neurons by defined factors.Nature 463:1035-1041.
Volz K(2008)The functional duality of iron regulatory protein 1.Curr Opin Struct Biol 18:106-111.
Yoo AS,Sun AX,Li L,Shcheglovitov A,Portmann T,Li Y,Lee-Messer C,Dolmetsch RE,Tsien RW,Crabtree GR(2011)MicroRNA-mediated conversion of human fibroblasts to neurons.Nature 476:228-231.
Yoon SJ,Koh YH,Floyd RA,Park JW(2000)Copper,zinc superoxide dismutase enhances DNA damage and mutagenicity induced by cysteine/iron.Mutat Res 448:97-104.
Zhang F,Dryhurst G(1994)Effects of L-cysteine on the oxidation chemistry of dopamine:new reaction pathways of potential relevance to idiopathic Parkinson’s disease.J Med Chem 37:1084-1098.
Zhang L,Yagnik G,Jiang D,Shi S,Chang P,Zhou F(2012)Separation of intermediates of iron-catalyzed dopamine oxidation reactions using reversed-phase ion-pairing chromatography coupled in tandem with UV-visible and ESI-MS detections.J Chromatogr B Analyt Technol Biomed Life Sci 911:55-58.
Zhang W,Phillips K,Wielgus AR,Liu J,Albertini A,Zucca FA,Faust R,Qian SY,Miller DS,Chignell CF,Wilson B,Jackson-Lewis V,Przedborski S,Joset D,Loike J,Hong JS,Sulzer D,Zecca L(2011)Neuromelanin activates microglia and induces degeneration of dopaminergic neurons:implications for progression of Parkinson’s disease.Neurotox Res 19:63-72.
Zizioli D,Tiso N,Guglielmi A,Saraceno C,Busolin G,Giuliani R,Khatri D,Monti E,Borsani G,Argenton F,Finazzi D(2016)Knockdown 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.
Zucca FA,Vanna R,Cupaioli FA,Bellei C,De Palma A,Di Silvestre D,Mauri P,Grassi S,Prinetti A,Casella L,Sulzer D,Zecca L(2018)Neuromelanin organelles are specialized autolysosomes that accumulate undegraded proteins and lipids in aging human brain and are likely involved in Parkinson’s disease.NPJ Parkinsons Dis 4:17.
álvarez-Córdoba M,Fernández Khoury A,Villanueva-Paz M,Gó-mez-Navarro C,Villalón-García I,Suárez-Rivero JM,Povea-Cabello S,de la Mata M,Cotán D,Talaverón-Rey M,Pérez-Pulido AJ,Salas JJ,Pérez-Villegas EM,Díaz-Quintana A,Armengol JA,Sánchez-Alcázar JA(2018)Pantothenate rescues iron accumulation in Pantothenate Kinase-associated neurodegeneration depending on the type of mutation.Mol Neurobiol doi:10.1007/s12035-018-1333-0.
Andreotti G,Guarracino MR,Cammisa M,Correra A,Cubellis MV(2010)Prediction of the responsiveness to pharmacological chaperones:lysosomal human alpha-galactosidase,a case of study.Orphanet J Rare Dis 5:36.
Andreotti G,Cabeza de Vaca I,Poziello A,Monti MC,Guallar V,Cubellis MV(2014)Conformational response to ligand binding in phosphomannomutase2:insights into inborn glycosylation disorder.J Biol Chem 289:34900-34910.
Bendikov-Bar I,Maor G,Filocamo M,Horowitz M(2013)Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase.Blood Cells Mol Dis 50:141-145.
Berman SB,Hastings TG(1999)Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria:implications for Parkinson’s disease.J Neurochem73:1127-1137.
Biosa A,Arduini I,Soriano ME,Giorgio V,Bernardi P,Bisaglia M,Bubacco L(2018)Dopamine oxidation products as mitochondrial endotoxins,a potential molecular mechanism for preferential neurodegeneration in Parkinson’s disease.ACS Chem Neurosci 9:2849-2858.
Bohic S,Murphy K,Paulus W,Cloetens P,Salome M,Susini J,Double K(2008)Intracellular chemical imaging of the developmental phases of human neuromelanin using synchrotron X-ray microspectroscopy.Anal Chem 80:9557-9566.
Bosveld F,Rana A,van der Wouden PE,Lemstra W,Ritsema M,Kampinga HH,Sibon OC(2008)De novo CoA biosynthesis is required to maintain DNA integrity during development of the Drosophila nervous system.Hum Mol Genet 17:2058-2069.
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 knockout mouse model.Hum Mol Genet 21:5294-5305.
Brunk UT,Terman A(2002)Lipofuscin:mechanisms of age-related accumulation and influence on cell function.Free Radic Biol Med33:611-619.
Campanella A,Privitera D,Guaraldo M,Rovelli E,Barzaghi C,Garavaglia B,Santambrogio P,Cozzi A,Levi S(2012)Skin fibroblasts from pantothenate kinase-associated neurodegeneration patients show altered cellular oxidative status and have defective iron-handling properties.Hum Mol Genet 21:4049-4059.
Colman A,Dreesen O(2009)Pluripotent stem cells and disease modeling.Cell Stem Cell 5:244-247.
Connolly GP(1998)Fibroblast models of neurological disorders:fluorescence measurement studies.Trends Pharmacol Sci 19:171-177.
Defendini R,Markesbery WR,Mastri AR,Duffy PE(1973)Hallervorden-Spatz disease and infantile neuroaxonal dystrophy.Ultrastructural observations,anatomical pathology and nosology.J Neurol Sci 20:7-23.
Di Meo I,Tiranti V(2018)Classification and molecular pathogenesis of NBIA syndromes.Eur J Paediatr Neurol 22:272-284.
Dolmetsch R,Geschwind DH(2011)The human brain in a dish:the promise of iPSC-derived neurons.Cell 145:831-834.
Double KL,Dedov VN,Fedorow H,Kettle E,Halliday GM,Garner B,Brunk UT(2008)The comparative biology of neuromelanin and lipofuscin in the human brain.Cell Mol Life Sci 65:1669-1682.
Drouin-Ouellet J,Lau S,Brattas PL,Rylander Ottosson D,Pircs K,Grassi DA,Collins LM,Vuono R,Andersson Sjoland A,Westergren-Thorsson G,Graff C,Minthon L,Toresson H,Barker RA,Jakobsson J,Parmar M(2017)REST suppression mediates neural conversion of adult human fibroblasts via microRNA-dependent and-independent pathways.EMBO Mol Med 9:1117-1131.
Frolova MS,Surin AM,Braslavski AV,Vekshin NL(2015)Degradation of mitochondria to lipofuscin upon heating and illumination.Biofizika 60:1125-1131.
Gerlach M,Riederer P,Double KL(2008)Neuromelanin-bound ferric iron as an experimental model of dopaminergic neurodegeneration in Parkinson’s disease.Parkinsonism Relat Disord 14 Suppl 2:S185-188.
Gerlach M,Double KL,Ben-Shachar D,Zecca L,Youdim MB,Riederer P(2003)Neuromelanin and its interaction with iron as a potential risk factor for dopaminergic neurodegeneration underlying Parkinson’s disease.Neurotox Res 5:35-44.
Goldin E,Zheng W,Motabar O,Southall N,Choi JH,Marugan J,Austin CP,Sidransky E(2012)High throughput screening for small molecule therapy for Gaucher disease using patient tissue as the source of mutant glucocerebrosidase.PLoS One 7:e29861.
Gregory A,Hayflick SJ(2005)Neurodegeneration with brain iron accumulation.Folia Neuropathol 43:286-296.
Gregory A,Polster BJ,Hayflick SJ(2009)Clinical and genetic delineation of neurodegeneration with brain iron accumulation.J Med Genet 46:73-80.
Hare DJ,Double KL(2016)Iron and dopamine:a toxic couple.Brain139:1026-1035.
Hay Mele B,Citro V,Andreotti G,Cubellis MV(2015)Drug repositioning can accelerate discovery of pharmacological chaperones.Orphanet J Rare Dis 10:55.
Hayflick SJ(2006)Neurodegeneration with brain iron accumulation:from genes to pathogenesis.Semin Pediatr Neurol 13:182-185.
Hayflick SJ,Westaway SK,Levinson B,Zhou B,Johnson MA,Ching KH,Gitschier J(2003)Genetic,clinical,and radiographic delineation of Hallervorden-Spatz syndrome.N Engl J Med 348:33-40.
H?hn A,Grune T(2013)Lipofuscin:formation,effects and role of macroautophagy.Redox Biol 1:140-144.
Horvath S(2013)DNA methylation age of human tissues and cell types.Genome Biol 14:R115.
Huang ML,Lane DJ,Richardson DR(2011)Mitochondrial mayhem:the mitochondrion as a modulator of iron metabolism and its role in disease.Antioxid Redox Signal 15:3003-3019.
Huh CJ,Zhang B,Victor MB,Dahiya S,Batista LF,Horvath S,Yoo AS(2016)Maintenance of age in human neurons generated by microR-NA-based neuronal conversion of fibroblasts.eLife 5:e18648.
Ishihara K,Okuyama S,Kumano S,Iida K,Hamana H,Murakoshi M,Kobayashi T,Usami S,Ikeda K,Haga Y,Tsumoto K,Nakamura H,Hirasawa N,Wada H(2010)Salicylate restores transport function and anion exchanger activity of missense pendrin mutations.Hear Res 270:110-118.
Johnson MA,Kuo YM,Westaway SK,Parker SM,Ching KH,Gitschier J,Hayflick SJ(2004)Mitochondrial localization of human PANK2and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration.Ann N Y Acad Sci 1012:282-298.
Jolly RD,Douglas BV,Davey PM,Roiri JE(1995)Lipofuscin in bovine muscle and brain:a model for studying age pigment.Gerontology 41Suppl 2:283-295.
Jung T,Bader N,Grune T(2007)Lipofuscin:formation,distribution,and metabolic consequences.Ann N Y Acad Sci 1119:97-111.
Karlsson O,Lindquist NG(2016)Melanin and neuromelanin binding of drugs and chemicals:toxicological implications.Arch Toxicol90:1883-1891.
Kim J,Basak JM,Holtzman DM(2009)The role of apolipoprotein E in Alzheimer’s disease.Neuron 63:287-303.
Koh HJ,Lee SM,Son BG,Lee SH,Ryoo ZY,Chang KT,Park JW,Park DC,Song BJ,Veech RL,Song H,Huh TL(2004)Cytosolic NAD-P+-dependent isocitrate dehydrogenase plays a key role in lipid metabolism.J Biol Chem 279:39968-39974.
Konig J,Ott C,Hugo M,Jung T,Bulteau AL,Grune T,Hohn A(2017)Mitochondrial contribution to lipofuscin formation.Redox Biol11:673-681.
Kruer MC(2013)The neuropathology of neurodegeneration with brain iron accumulation.Int Rev Neurobiol 110:165-194.
Kuo YM,Hayflick SJ,Gitschier J(2007)Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase-associated neurodegeneration.J Inherit Metab Dis 30:310-317.
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.
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.
Kurz T,Terman A,Gustafsson B,Brunk UT(2008)Lysosomes and oxidative stress in aging and apoptosis.Biochim Biophys Acta1780:1291-1303.
Ladewig J,Koch P,Brustle O(2013)Leveling Waddington:the emergence of direct programming and the loss of cell fate hierarchies.Nat Rev Mol Cell Biol 14:225-236.
Ladewig J,Mertens J,Kesavan J,Doerr J,Poppe D,Glaue F,Herms S,Wernet P,Kogler G,Muller FJ,Koch P,Brustle O(2012)Small molecules enable highly efficient neuronal conversion of human fibroblasts.Nat Methods 9:575-578.
Lan AP,Chen J,Chai ZF,Hu Y(2016)The neurotoxicity of iron,copper and cobalt in Parkinson’s disease through ROS-mediated mechanisms.Biometals 29:665-678.
Leonardi R,Zhang YM,Lykidis A,Rock CO,Jackowski S(2007)Localization and regulation of mouse pantothenate kinase 2.FEBS Lett581:4639-4644.
Levi S,Finazzi D(2014)Neurodegeneration with brain iron accumulation:update on pathogenic mechanisms.Front Pharmacol 5:99.
Lill R,Srinivasan V,Muhlenhoff U(2014)The role of mitochondria in cytosolic-nuclear iron-sulfur protein biogenesis and in cellular iron regulation.Curr Opin Microbiol 22:111-119.
Lu C,Cortopassi G(2007)Frataxin knockdown causes loss of cytoplasmic iron-sulfur cluster functions,redox alterations and induction of heme transcripts.Arch Biochem Biophys 457:111-122.
Luckenbach MW,Green WR,Miller NR,Moser HW,Clark AW,Tennekoon G(1983)Ocular clinicopathologic correlation of Hallervorden-Spatz syndrome with acanthocytosis and pigmentary retinopathy.Am J Ophthalmol 95:369-382.
Maegawa GH,Tropak M,Buttner J,Stockley T,Kok F,Clarke JT,Mahuran DJ(2007)Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis.J Biol Chem 282:9150-9161.
Maitra R,Hamilton JW(2007)Altered biogenesis of deltaF508-CFTR following treatment with doxorubicin.Cell Physiol Biochem 20:465-472.
Martin GM,Chen PC,Devaraneni P,Shyng SL(2013)Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels.Front Physiol 4:386.
Matsunaga T,Kotamraju S,Kalivendi SV,Dhanasekaran A,Joseph J,Kalyanaraman B(2004)Ceramide-induced intracellular oxidant formation,iron signaling,and apoptosis in endothelial cells:protective role of endogenous nitric oxide.J Biol Chem 279:28614-28624.
Mertens J,Paquola ACM,Ku M,Hatch E,Bohnke L,Ladjevardi S,McGrath S,Campbell B,Lee H,Herdy JR,Goncalves JT,Toda T,Kim Y,Winkler J,Yao J,Hetzer MW,Gage FH(2015)Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects.Cell Stem Cell 17:705-718.
Miura K,Okada Y,Aoi T,Okada A,Takahashi K,Okita K,Nakagawa M,Koyanagi M,Tanabe K,Ohnuki M,Ogawa D,Ikeda E,Okano H,Yamanaka S(2009)Variation in the safety of induced pluripotent stem cell lines.Nat Biotechnol 27:743-745.
Napolitano A,Crescenzi O,Pezzella A,Prota G(1995)Generation of the neurotoxin 6-hydroxydopamine by peroxidase/H2O2 oxidation of dopamine.J Med Chem 38:917-922.
Newton CL,Whay AM,McArdle CA,Zhang M,van Koppen CJ,van de Lagemaat R,Segaloff DL,Millar RP(2011)Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist.Proc Natl Acad Sci U S A 108:7172-7176.
Nunez MT,Urrutia P,Mena N,Aguirre P,Tapia V,Salazar J(2012)Iron toxicity in neurodegeneration.Biometals 25:761-776.
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.
Pang ZP,Yang N,Vierbuchen T,Ostermeier A,Fuentes DR,Yang TQ,Citri A,Sebastiano V,Marro S,Sudhof TC,Wernig M(2011)Induction of human neuronal cells by defined transcription factors.Nature 476:220-223.
Park BE,Netsky MG,Betsill WL,Jr.(1975)Pathogenesis of pigment and spheroid formation in Hallervorden-Spatz syndrome and related disorders.Neurology 25:1172-1178.
Perry TL,Norman MG,Yong VW,Whiting S,Crichton JU,Hansen S,Kish SJ(1985)Hallervorden-Spatz disease:cysteine accumulation and cysteine dioxygenase deficiency in the globus pallidus.Ann Neurol 18:482-489.
Pezzella A,d’Ischia M,Napolitano A,Misuraca G,Prota G(1997)Iron-mediated generation of the neurotoxin 6-hydroxydopamine quinone by reaction of fatty acid hydroperoxides with dopamine:a possible contributory mechanism for neuronal degeneration in Parkinson’s disease.J Med Chem 40:2211-2216.
Pfisterer U,Ek F,Lang S,Soneji S,Olsson R,Parmar M(2016)Small molecules increase direct neural conversion of human fibroblasts.Sci Rep 6:38290.
Poli M,Derosas M,Luscieti S,Cavadini P,Campanella A,Verardi R,Finazzi D,Arosio P(2010)Pantothenate kinase-2(Pank2)silencing causes cell growth reduction,cell-specific ferroportin upregulation and iron deregulation.Neurobiol Dis 39:204-210.
Porto C,Ferrara MC,Meli M,Acampora E,Avolio V,Rosa M,Cobucci-Ponzano B,Colombo G,Moracci M,Andria G,Parenti G(2012)Pharmacological enhancement of alpha-glucosidase by the allosteric chaperone N-acetylcysteine.Mol Ther 20:2201-2211.
Powell SR,Wang P,Divald A,Teichberg S,Haridas V,McCloskey TW,Davies KJ,Katzeff H(2005)Aggregates of oxidized proteins(lipofuscin)induce apoptosis through proteasome inhibition and dysregulation of proapoptotic proteins.Free Radic Biol Med 38:1093-1101.
Rana A,Seinen E,Siudeja K,Muntendam R,Srinivasan B,van der Want JJ,Hayflick S,Reijngoud DJ,Kayser O,Sibon OC(2010)Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration.Proc Natl Acad Sci U S A 107:6988-6993.
Reeg S,Grune T(2015)Protein oxidation in aging:does it play a role in aging progression?Antioxid Redox Signal 23:239-255.
Rigat B,Mahuran D(2009)Diltiazem,a L-type Ca(2+)channel blocker,also acts as a pharmacological chaperone in Gaucher patient cells.Mol Genet Metab 96:225-232.
Salvador GA,Uranga RM,Giusto NM(2010)Iron and mechanisms of neurotoxicity.Int J Alzheimers Dis 2011:720658.
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.
Schee Genannt Halfmann S,Mahlmann L,Leyens L,Reumann M,Brand A(2017)Personalized medicine:what’s in it for rare diseases?Adv Exp Med Biol 1031:387-404.
Strafella C,Caputo V,Galota MR,Zampatti S,Marella G,Mauriello S,Cascella R,Giardina E(2018)Application of precision medicine in neurodegenerative diseases.Front Neurol 9:701.
Sulzer D,Bogulavsky J,Larsen KE,Behr G,Karatekin E,Kleinman MH,Turro N,Krantz D,Edwards RH,Greene LA,Zecca L(2000)Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles.Proc Natl Acad Sci U SA 97:11869-11874.
Swaiman KF,Smith SA,Trock GL,Siddiqui AR(1983)Sea-blue histiocytes,lymphocytic cytosomes,movement disorder and 59Fe-uptake in basal ganglia:Hallervorden-Spatz disease or ceroid storage disease with abnormal isotope scan?Neurology 33:301-305.
Tan L,Jiang T,Tan L,Yu JT(2016)Toward precision medicine in neurological diseases.Ann Transl Med 4:104.
Tello C,Darling A,Lupo V,Perez-Duenas B,Espinos C(2018)On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation.Clin Genet 93:731-740.
Titova N,Chaudhuri KR(2017)Personalized medicine in Parkinson’s disease:Time to be precise.Mov Disord 32:1147-1154.
Tong WH,Rouault TA(2007)Metabolic regulation of citrate and iron by aconitases:role of iron-sulfur cluster biogenesis.Biometals20:549-564.
Torper O,Pfisterer U,Wolf DA,Pereira M,Lau S,Jakobsson J,Bj?rklund A,Grealish S,Parmar M(2013)Generation of induced neurons via direct conversion in vivo.Proc Natl Acad Sci U S A110:7038-7043.
Vierbuchen T,Ostermeier A,Pang ZP,Kokubu Y,Südhof TC,Wernig M(2010)Direct conversion of fibroblasts to functional neurons by defined factors.Nature 463:1035-1041.
Volz K(2008)The functional duality of iron regulatory protein 1.Curr Opin Struct Biol 18:106-111.
Yoo AS,Sun AX,Li L,Shcheglovitov A,Portmann T,Li Y,Lee-Messer C,Dolmetsch RE,Tsien RW,Crabtree GR(2011)MicroRNA-mediated conversion of human fibroblasts to neurons.Nature 476:228-231.
Yoon SJ,Koh YH,Floyd RA,Park JW(2000)Copper,zinc superoxide dismutase enhances DNA damage and mutagenicity induced by cysteine/iron.Mutat Res 448:97-104.
Zhang F,Dryhurst G(1994)Effects of L-cysteine on the oxidation chemistry of dopamine:new reaction pathways of potential relevance to idiopathic Parkinson’s disease.J Med Chem 37:1084-1098.
Zhang L,Yagnik G,Jiang D,Shi S,Chang P,Zhou F(2012)Separation of intermediates of iron-catalyzed dopamine oxidation reactions using reversed-phase ion-pairing chromatography coupled in tandem with UV-visible and ESI-MS detections.J Chromatogr B Analyt Technol Biomed Life Sci 911:55-58.
Zhang W,Phillips K,Wielgus AR,Liu J,Albertini A,Zucca FA,Faust R,Qian SY,Miller DS,Chignell CF,Wilson B,Jackson-Lewis V,Przedborski S,Joset D,Loike J,Hong JS,Sulzer D,Zecca L(2011)Neuromelanin activates microglia and induces degeneration of dopaminergic neurons:implications for progression of Parkinson’s disease.Neurotox Res 19:63-72.
Zizioli D,Tiso N,Guglielmi A,Saraceno C,Busolin G,Giuliani R,Khatri D,Monti E,Borsani G,Argenton F,Finazzi D(2016)Knockdown 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.
Zucca FA,Vanna R,Cupaioli FA,Bellei C,De Palma A,Di Silvestre D,Mauri P,Grassi S,Prinetti A,Casella L,Sulzer D,Zecca L(2018)Neuromelanin organelles are specialized autolysosomes that accumulate undegraded proteins and lipids in aging human brain and are likely involved in Parkinson’s disease.NPJ Parkinsons Dis 4:17.