CoChat
Sign Up
Cited by 126Genetics and Neurodevelopmental DisordersRedox biology and oxidative stressGenetic Neurodegenerative Diseases

Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome

Open access
De Felice, Claudio, Della Ragione, Floriana, Signorini, Cinzia, Leoncini, Silvia, Pecorelli, Alessandra, Ciccoli, Lucia, Scalabrì, Francesco, Marracino, Federico +15 more·2014·Neurobiology of Disease
DOI 10.1016/j.nbd.2014.04.006PMC PMC4076513
Open this paper in CoChat — free accountOpen PDF

Abstract

Rett syndrome (RTT) is a rare neurodevelopmental disorder affecting almost exclusively females, caused in the overwhelming majority of the cases by loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). High circulating levels of oxidative stress (OS) markers in patients suggest the involvement of OS in the RTT pathogenesis. To investigate the occurrence of oxidative brain damage in Mecp2 mutant mouse models, several OS markers were evaluated in whole brains of Mecp2-null (pre-symptomatic, symptomatic, and rescued) and Mecp2-308 mutated (pre-symptomatic and symptomatic) mice, and compared to those of wild type littermates. Selected OS markers included non-protein-bound iron, isoprostanes (F2-isoprostanes, F4-neuroprostanes, F2-dihomo-isoprostanes) and 4-hydroxy-2-nonenal protein adducts. Our findings indicate that oxidative brain damage 1) occurs in both Mecp2-null (both -/y and stop/y) and Mecp2-308 (both 308/y males and 308/+ females) mouse models of RTT; 2) precedes the onset of symptoms in both Mecp2-null and Mecp2-308 models; and 3) is rescued by Mecp2 brain specific gene reactivation. Our data provide direct evidence of the link between Mecp2 deficiency, oxidative stress and RTT pathology, as demonstrated by the rescue of the brain oxidative homeostasis following brain-specifically Mecp2-reactivated mice. The present study indicates that oxidative brain damage is a previously unrecognized hallmark feature of murine RTT, and suggests that Mecp2 is involved in the protection of the brain from oxidative stress.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.nbd.2014.04.006

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • RTT animal models have oxidative changes in the brain.

    “RTT patients have increased oxidative burden and abnormal mitochondrial structure, while RTT animal models have defects in the mitochondrial respiratory chain [23,26,200–202] and oxidative changes in the brain [203].”

    From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [203]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 79 · Cited by 126

Research works printed but not linked: 66

  1. Amir R.E. Van den Veyver I.B. Wan M. Tran C.Q. Francke U. Zoghbi H.Y. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 Nat. Genet. 23 1999 185 188 10508514
  2. Bertulat B. De Bonis M.L. Della Ragione F. Lehmkuhl A. Milden M. Storm C. Jost K.L. Scala S. Hendrich B. D'Esposito M. Cardoso M.C. MeCP2 dependent heterochromatin reorganization during neural differentiation of a novel Mecp2-deficient embryonic stem cell reporter line PLoS One 7 2012 e47848 23112857 PMC3480415
  3. Bienvenu T. Chelly J. Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized Nat. Rev. Genet. 7 2006 415 426 16708070
  4. Burford B. Kerr A.M. Macleod H.A. Nurse recognition of early deviation in development in home videos of infants with Rett disorder J. Intellect. Disabil. Res. 47 2003 588 596 14641806
  5. Calfa G. Percy A.K. Pozzo-Miller L. Experimental models of Rett syndrome based on Mecp2 dysfunction Exp. Biol. Med. (Maywood) 236 2011 3 19 21239731 PMC3059199
  6. Chahrour M. Zoghbi H.Y. The story of Rett syndrome: from clinic to neurobiology Neuron 56 2007 422 437 17988628
  7. Ciccoli L. Leoncini S. Signorini C. Comporti M. Iron and erythrocytes: physiological and pathophysiological aspects Valacchi G. Davis P. Oxidant in Biology: A Question of Balance 2008 Springer 167 181
  8. De Felice C. Ciccoli L. Leoncini S. Signorini C. Rossi M. Vannuccini L. Guazzi G. Latini G. Comporti M. Valacchi G. Hayek J. Systemic oxidative stress in classic Rett syndrome Free Radic. Biol. Med. 47 2009 440 448 19464363
  9. De Felice C. Guazzi G. Rossi M. Ciccoli L. Signorini C. Leoncini S. Tonni G. Latini G. Valacchi G. Hayek J. Unrecognized lung disease in classic Rett syndrome: a physiologic and high-resolution CT imaging study Chest 138 2010 386 392 20348192
  10. De Felice C. Signorini C. Durand T. Oger C. Guy A. Bultel-Ponce V. Galano J.M. Ciccoli L. Leoncini S. D'Esposito M. Filosa S. Pecorelli A. Valacchi G. Hayek J. F2-dihomo-isoprostanes as potential early biomarkers of lipid oxidative damage in Rett syndrome J. Lipid Res. 52 2011 2287 2297 21917727 PMC3283260
  11. De Felice C. Signorini C. Durand T. Ciccoli L. Leoncini S. D'Esposito M. Filosa S. Oger C. Guy A. Bultel-Ponce V. Galano J.M. Pecorelli A. De Felice L. Valacchi G. Hayek J. Partial rescue of Rett syndrome by omega-3 polyunsaturated fatty acids (PUFAs) oil Genes Nutr. 7 2012 447 458 22399313 PMC3380188
  12. De Felice C. Signorini C. Leoncini S. Pecorelli A. Durand T. Valacchi G. Ciccoli L. Hayek J. The role of oxidative stress in Rett syndrome: an overview Ann. N. Y. Acad. Sci. 1259 2012 121 135 22758644
  13. De Felice C. Rossi M. Leoncini S. Chisci G. Signorini C. Lonetti G. Vannuccini L. Spina D. Ginori A. Iacona I. Cortelazzo A. Pecorelli A. Valacchi G. Ciccoli L. Pizzorusso T. Hayek J. Inflammatory lung disease in Rett syndrome Mediat. Inflamm. 2014 2014 560120 PMC3976920 24757286
  14. De Filippis B. Ricceri L. Laviola G. Early postnatal behavioral changes in the Mecp2-308 truncation mouse model of Rett syndrome Genes Brain Behav. 9 2010 213 223 19958389
  15. Delepine C. Nectoux J. Bahi-Buisson N. Chelly J. Bienvenu T. MeCP2 deficiency is associated with impaired microtubule stability FEBS Lett. 587 2013 245 253 23238081
  16. Derecki N.C. Cronk J.C. Lu Z. Xu E. Abbott S.B. Guyenet P.G. Kipnis J. Wild-type microglia arrest pathology in a mouse model of Rett syndrome Nature 484 2012 105 109 22425995 PMC3321067
  17. Derecki N.C. Cronk J.C. Kipnis J. The role of microglia in brain maintenance: implications for Rett syndrome Trends Immunol. 34 2013 144 150 23122051 PMC3566274
  18. Durand T. De Felice C. Signorini C. Oger C. Bultel-Ponce V. Guy A. Galano J.M. Leoncini S. Ciccoli L. Pecorelli A. Valacchi G. Hayek J. F(2)-dihomo-isoprostanes and brain white matter damage in stage 1 Rett syndrome Biochimie 95 2013 86 90 23009927
  19. Einspieler C. Kerr A.M. Prechtl H.F. Abnormal general movements in girls with Rett disorder: the first four months of life Brain Dev. 27 Suppl. 1 2005 S8 S13 16182501
  20. Einspieler C. Kerr A.M. Prechtl H.F. Is the early development of girls with Rett disorder really normal? Pediatr. Res. 57 2005 696 700 15718369
  21. Ferguson L.R. Chronic inflammation and mutagenesis Mutat. Res. 690 2010 3 11 20223251
  22. Galano J.M. Mas E. Barden A. Mori T.A. Signorini C. De Felice C. Barrett A. Opere C. Pinot E. Schwedhelm E. Benndorf R. Roy J. Le Guennec J.Y. Oger C. Durand T. Isoprostanes and neuroprostanes: total synthesis, biological activity and biomarkers of oxidative stress in humans Prostaglandins Other Lipid Mediat. 107 2013 95 102 23644158
  23. Garg S.K. Lioy D.T. Cheval H. McGann J.C. Bissonnette J.M. Murtha M.J. Foust K.D. Kaspar B.K. Bird A. Mandel G. Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome J. Neurosci. 33 2013 13612 13620 23966684 PMC3755711
  24. Goffin D. Allen M. Zhang L. Amorim M. Wang I.T. Reyes A.R. Mercado-Berton A. Ong C. Cohen S. Hu L. Blendy J.A. Carlson G.C. Siegel S.J. Greenberg M.E. Zhou Z. Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses Nat. Neurosci. 15 2012 274 283 22119903 PMC3267879
  25. Grillo E. Lo Rizzo C. Bianciardi L. Bizzarri V. Baldassarri M. Spiga O. Furini S. De Felice C. Signorini C. Leoncini S. Pecorelli A. Ciccoli L. Mencarelli M.A. Hayek J. Meloni I. Ariani F. Mari F. Renieri A. Revealing the complexity of a monogenic disease: Rett syndrome exome sequencing PLoS One 8 2013 e56599 23468869 PMC3585308
  26. Grosser E. Hirt U. Janc O.A. Menzfeld C. Fischer M. Kempkes B. Vogelgesang S. Manzke T.U. Opitz L. Salinas-Riester G. Muller M. Oxidative burden and mitochondrial dysfunction in a mouse model of Rett syndrome Neurobiol. Dis. 48 2012 102 114 22750529
  27. Guy J. Hendrich B. Holmes M. Martin J.E. Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome Nat. Genet. 27 2001 322 326 11242117
  28. Guy J. Gan J. Selfridge J. Cobb S. Bird A. Reversal of neurological defects in a mouse model of Rett syndrome Science 315 2007 1143 1147 17289941 PMC7610836
  29. Guy J. Cheval H. Selfridge J. Bird A. The role of MeCP2 in the brain Annu. Rev. Cell Dev. Biol. 27 2011 631 652 21721946
  30. Hagberg B. Clinical manifestations and stages of Rett syndrome Ment. Retard. Dev. Disabil. Res. Rev. 8 2002 61 65 12112728
  31. Halliwell B. Gutteridge J. Free Radicals in Biology and Medicine Fourth edition 2007 Oxford University Press
  32. Han K. Gennarino V.A. Lee Y. Pang K. Hashimoto-Torii K. Choufani S. Raju C.S. Oldham M.C. Weksberg R. Rakic P. Liu Z. Zoghbi H.Y. Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p Genes Dev. 27 2013 485 490 23431031 PMC3605462
  33. Janc O.A. Muller M. The free radical scavenger Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance in a mouse model of Rett syndrome Front. Cell. Neurosci. 8 2014 56 24605086 PMC3932407
  34. Jones P.L. Veenstra G.J. Wade P.A. Vermaak D. Kass S.U. Landsberger N. Strouboulis J. Wolffe A.P. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription Nat. Genet. 19 1998 187 191 9620779
  35. Katz D.M. Berger-Sweeney J.E. Eubanks J.H. Justice M.J. Neul J.L. Pozzo-Miller L. Blue M.E. Christian D. Crawley J.N. Giustetto M. Guy J. Howell C.J. Kron M. Nelson S.B. Samaco R.C. Schaevitz L.R. St Hillaire-Clarke C. Young J.L. Zoghbi H.Y. Mamounas L.A. Preclinical research in Rett syndrome: setting the foundation for translational success Dis. Model Mech. 5 2012 733 745 23115203 PMC3484856
  36. Leonard H. Bower C. Is the girl with Rett syndrome normal at birth? Dev. Med. Child Neurol. 40 1998 115 121 9489500
  37. Leoncini S. De Felice C. Signorini C. Pecorelli A. Durand T. Valacchi G. Ciccoli L. Hayek J. Oxidative stress in Rett syndrome: natural history, genotype, and variants Redox Rep. 16 2011 145 153 21888765 PMC6837451
  38. Lioy D.T. Garg S.K. Monaghan C.E. Raber J. Foust K.D. Kaspar B.K. Hirrlinger P.G. Kirchhoff F. Bissonnette J.M. Ballas N. Mandel G. A role for glia in the progression of Rett's syndrome Nature 475 2011 497 500 21716289 PMC3268776
  39. Moretti P. Bouwknecht J.A. Teague R. Paylor R. Zoghbi H.Y. Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome Hum. Mol. Genet. 14 2005 205 220 15548546
  40. Moretti P. Levenson J.M. Battaglia F. Atkinson R. Teague R. Antalffy B. Armstrong D. Arancio O. Sweatt J.D. Zoghbi H.Y. Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome J. Neurosci. 26 2006 319 327 16399702 PMC6674314
  41. Nagy G. Ackerman S.L. Cholesterol metabolism and Rett syndrome pathogenesis Nat. Genet. 45 2013 965 967 23985682
  42. Neul J.L. Kaufmann W.E. Glaze D.G. Christodoulou J. Clarke A.J. Bahi-Buisson N. Leonard H. Bailey M.E. Schanen N.C. Zappella M. Renieri A. Huppke P. Percy A.K. Rett syndrome: revised diagnostic criteria and nomenclature Ann. Neurol. 68 2010 944 950 21154482 PMC3058521
  43. Pecorelli A. Ciccoli L. Signorini C. Leoncini S. Giardini A. D'Esposito M. Filosa S. Hayek J. De Felice C. Valacchi G. Increased levels of 4HNE-protein plasma adducts in Rett syndrome Clin. Biochem. 44 2011 368 371 21276437
  44. Pecorelli A. Leoncini S. De Felice C. Signorini C. Cerrone C. Valacchi G. Ciccoli L. Hayek J. Non-protein-bound iron and 4-hydroxynonenal protein adducts in classic autism Brain Dev. 35 2013 146 154 22534237
  45. Picker J.D. Yang R. Ricceri L. Berger-Sweeney J. An altered neonatal behavioral phenotype in Mecp2 mutant mice Neuroreport 17 2006 541 544 16543822
  46. Poli G. Schaur R.J. Siems W.G. Leonarduzzi G. 4-Hydroxynonenal: a membrane lipid oxidation product of medicinal interest Med. Res. Rev. 28 2008 569 631 18058921
  47. Praticò D. The neurobiology of isoprostanes and Alzheimer's disease Biochim. Biophys. Acta 1801 2010 930 933 20116452
  48. Ramirez J.M. Ward C.S. Neul J.L. Breathing challenges in Rett syndrome: lessons learned from humans and animal models Respir. Physiol. Neurobiol. 189 2013 280 287 23816600 PMC3812329
  49. Rett A. On a unusual brain atrophy syndrome in hyperammonemia in childhood Wien. Med. Wochenschr. 116 1966 723 726 5300597
  50. Ricceri L. De Filippis B. Laviola G. Mouse models of Rett syndrome: from behavioural phenotyping to preclinical evaluation of new therapeutic approaches Behav. Pharmacol. 19 2008 501 517 18690105
  51. Robinson L. Guy J. McKay L. Brockett E. Spike R.C. Selfridge J. De Sousa D. Merusi C. Riedel G. Bird A. Cobb S.R. Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome Brain 135 2012 2699 2710 22525157 PMC3437019
  52. Rouault T.A. Iron metabolism in the CNS: implications for neurodegenerative diseases Nat. Rev. Neurosci. 14 2013 551 564 23820773
  53. Santos M. Silva-Fernandes A. Oliveira P. Sousa N. Maciel P. Evidence for abnormal early development in a mouse model of Rett syndrome Genes Brain Behav. 6 2007 277 286 16848781
  54. Schroder N. Figueiredo L.S. de Lima M.N. Role of brain iron accumulation in cognitive dysfunction: evidence from animal models and human studies J. Alzheimer's Dis. 34 2013 797 812 23271321
  55. Shahbazian M. Young J. Yuva-Paylor L. Spencer C. Antalffy B. Noebels J. Armstrong D. Paylor R. Zoghbi H. Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3 Neuron 35 2002 243 254 12160743
  56. Sierra C. Vilaseca M.A. Brandi N. Artuch R. Mira A. Nieto M. Pineda M. Oxidative stress in Rett syndrome Brain Dev. 23 Suppl. 1 2001 S236 S239 11738881
  57. Signorini C. Comporti M. Giorgi G. Ion trap tandem mass spectrometric determination of F2-isoprostanes J. Mass Spectrom. 38 2003 1067 1074 14595856
  58. Signorini C. Ciccoli L. Leoncini S. Carloni S. Perrone S. Comporti M. Balduini W. Buonocore G. Free iron, total F-isoprostanes and total F-neuroprostanes in a model of neonatal hypoxic–ischemic encephalopathy: neuroprotective effect of melatonin J. Pineal Res. 46 2009 148 154 19141088
  59. Signorini C. De Felice C. Leoncini S. Giardini A. D'Esposito M. Filosa S. Della Ragione F. Rossi M. Pecorelli A. Valacchi G. Ciccoli L. Hayek J. F(4)-neuroprostanes mediate neurological severity in Rett syndrome Clin. Chim. Acta 412 2011 1399 1406 21530498
  60. Signorini C. De Felice C. Durand T. Oger C. Galano J.M. Leoncini S. Pecorelli A. Valacchi G. Ciccoli L. Hayek J. Isoprostanes and 4-hydroxy-2-nonenal: markers or mediators of disease? Focus on Rett syndrome as a model of autism spectrum disorder Oxid. Med. Cell. Longev. 2013 2013 343824 23844273 PMC3697420
  61. Singh M. Dang T.N. Arseneault M. Ramassamy C. Role of by-products of lipid oxidation in Alzheimer's disease brain: a focus on acrolein J. Alzheimer's Dis. 21 2010 741 756 20634576
  62. Temudo T. Maciel P. Sequeiros J. Abnormal movements in Rett syndrome are present before the regression period: a case study Mov. Disord. 22 2007 2284 2287 17914728
  63. Tronche F. Kellendonk C. Kretz O. Gass P. Anlag K. Orban P.C. Bock R. Klein R. Schutz G. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety Nat. Genet. 23 1999 99 103 10471508
  64. Weaving L.S. Ellaway C.J. Gecz J. Christodoulou J. Rett syndrome: clinical review and genetic update J. Med. Genet. 42 2005 1 7 15635068 PMC1735910
  65. Yazdani M. Deogracias R. Guy J. Poot R.A. Bird A. Barde Y.A. Disease modeling using embryonic stem cells: MeCP2 regulates nuclear size and RNA synthesis in neurons Stem Cells 30 2012 2128 2139 22865604
  66. Zachariah R.M. Olson C.O. Ezeonwuka C. Rastegar M. Novel MeCP2 isoform-specific antibody reveals the endogenous MeCP2E1 expression in murine brain, primary neurons and astrocytes PLoS One 7 2012 e49763 23185431 PMC3501454

Authors
De Felice, C., Della Ragione, F., Signorini, C., Leoncini, S., Pecorelli, A., Ciccoli, L., Scalabrì, F., Marracino, F., Madonna, M., Belmonte, G., Ricceri, L., De Filippis, B., Laviola, G., Valacchi, G., Durand, T., Galano, J.-M., Oger, C., Guy, A., Bultel-Poncé, V., Guy, J., Filosa, S., Hayek, J., & D'Esposito, M.
Affiliations
  • University of Siena (IT)
  • Istituto Neurologico Mediterraneo (IT)
  • Istituto Superiore di Sanità (IT)
  • University of Ferrara (IT)
  • École Nationale Supérieure de Chimie de Montpellier (FR)
  • Wellcome Centre for Cell Biology (GB)
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2014-08
Volume
68
Pages
66-77
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2014.04.006
PMC
PMC4076513
OpenAlex
W2012807815
Cited by
126
References
79
Citations by year
2026: 1 · 2025: 7 · 2024: 9 · 2023: 9 · 2022: 8 · 2021: 11 · 2020: 11 · 2019: 13 · 2018: 11 · 2017: 17 · 2016: 9 · 2015: 16 · 2014: 4
FWCI
10.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
  • Use Siena air (University of Siena) (submittedVersion)
Funders
  • Bando Salute (TR142, Italy)
  • AIR
  • UE Initial Training Network (238242)
  • MIUR-CNR
  • IRE-IFO
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
Rett syndrome, MeCP2, oxidative stress, brain oxidative damage, Mecp2-null mice, isoprostanes, neuroprostanes, non-protein-bound iron, neurodevelopmental disorders
MeSH terms
Aldehydes, Analysis of Variance, Animals, Brain Injuries, Disease Models, Animal, Docosahexaenoic Acids, Female, Male, Gas Chromatography-Mass Spectrometry, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Rett Syndrome, Arachidonic Acid, Oxidative Stress, Isoprostanes, Mice, Methyl-CpG-Binding Protein 2, Neuroprostanes, Nestin

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review