Skip to main content
SpringerLink
Log in

Effects of Irradiation on the Postnatal Development of the Brain in a Genetic Mouse Model of Globoid Cell Leukodystrophy

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Irradiation is one way to condition Twitcher mice––a natural model of globoid cell leukodystrophy (GLD)––prior to receive bone marrow transplantation (BMT). BMT showed to delay but not to completely prevent GLD disease in treated mutants. The reasons why BMT is not completely preventive in Twitchers are unclear but we speculate that irradiation might contribute to worsen the neurological impairments generated by the disease by altering postnatal neurogenesis. To test this hypothesis, we examined proliferation, migration and differentiation of neural precursors in neurogenic areas of the Twitcher brain after exposure of 5 day-old mutant pups to 620 rad, a non-lethal dose that leads to 80–90% of bone-marrow engraftment in classic BMT. Twitchers showed to be sensitive to irradiation, leading to a severe retardation of body growth of irradiated mutants. Irradiated Twitchers had reduced proliferation of neural precursors and increased astrogliosis and microgliosis, with reduced numbers of migratory neuroblasts and significantly less brain myelination. These effects were accompanied by caspase-3 activation and appeared largely irreversible in the lifespan of the Twitcher. Our work confirms that exposure of the neonatal brain to irradiation conditions such as those performed prior to BMT, can lead to long-lasting alterations of postnatal neurogenesis and myelination, which might contribute to worsen the progression of disease in these myelin mutants and to reduce the success of BMT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Wenger DA, Suzuki K, Suzuki Y, Suzuki K (2001) Galactosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease). In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B (eds) The metabolic and molecular bases of inherited disease. McGraw–Hill, New York, pp 3669–3687

  2. Suzuki K, Suzuki K (1983) The twitcher mouse. A model of human globoid cell leukodystrophy (Krabbe’s disease). Am J Pathol 111:394–397

    PubMed  CAS  Google Scholar 

  3. Dolcetta D, Amadio S, Guerrini U, Givogri MI, Perani L, Galbiati F, Sironi L, Del Carro U, Roncarolo MG, Bongarzone E (2005) Myelin deterioration in Twitcher mice: motor evoked potentials and magnetic resonance imaging as in vivo monitoring tools. J Neurosci Res 81:597–604

    Article  PubMed  CAS  Google Scholar 

  4. Dolcetta D, Perani L, Givogri MI, Galbiati F, Amadio S, Del Carro U, Finocchiaro G, Fanzani A, Marchesini S, Naldini L, Roncarolo MG, Bongarzone E (2006) Design and optimization of lentiviral vectors for transfer of GALC expression in the Twitcher brain. J Gene Med 8:962–971

    Article  PubMed  CAS  Google Scholar 

  5. Igisu H, Suzuki K (1984) Progressive accumulation of toxic metabolite in a genetic leukodystrophy. Science 224:753–755

    Article  PubMed  CAS  Google Scholar 

  6. Suzuki K (1998) Twenty five years of the psychosine hypothesis: a personal perspective of its history and present status. Neurochem Res 23:251–259

    Article  PubMed  CAS  Google Scholar 

  7. Taniike M, Mohri I, Eguchi N, Irikura D, Urade Y, Okada S, Suzuki K (1999) An apoptotic depletion of oligodendrocytes in the twitcher, a murine model of globoid cell leukodystrophy. J Neuropathol Exp Neurol 58:644–653

    PubMed  CAS  Google Scholar 

  8. Zaka M, Wenger DA (2004) Psychosine-induced apoptosis in a mouse oligodendrocyte progenitor cell line is mediated by caspase activation. Neurosci Lett 358:205–209

    Article  PubMed  CAS  Google Scholar 

  9. Neufeld EF, Fratantoni JC (1970) Inborn errors of mucopolysaccharide metabolism. Science 169:141–146

    Article  PubMed  CAS  Google Scholar 

  10. Sando GN, Neufeld EF (1977) Recognition and receptor-mediated uptake of a lysosomal enzyme, alpha-l-iduronidase, by cultured human fibroblasts. Cell 12:619–627

    Article  PubMed  CAS  Google Scholar 

  11. Strisciuglio P, Creek KE, Sly WS (1984) Complementation, cross correction, and drug correction studies of combined beta-galactosidase neuraminidase deficiency in human fibroblasts. Pediatr Res 18:167–171

    PubMed  CAS  Google Scholar 

  12. Taylor RM, Wolfe JH (1994) Cross-correction of beta-glucuronidase deficiency by retroviral vector-mediated gene transfer. Exp Cell Res 214:606–613

    Article  PubMed  CAS  Google Scholar 

  13. Yeager AM, Brennan S, Tiffany C, Moser HW, Santos GW (1984) Prolonged survival and remyelination after hematopoietic cell transplantation in the twitcher mouse. Science 225:1052–1054

    Article  PubMed  CAS  Google Scholar 

  14. Yeager AM, Shinohara M, Shinn C (1991) Hematopoietic cell transplantation after administration of high-dose busulfan in murine globoid cell leukodystrophy (the twitcher mouse). Pediatr Res 29:302–305

    PubMed  CAS  Google Scholar 

  15. Yeager AM, Shinn C, Shinohara M, Pardoll DM (1993) Hematopoietic cell transplantation in the twitcher mouse. The effects of pretransplant conditioning with graded doses of busulfan. Transplantation 56:185–190

    Article  PubMed  CAS  Google Scholar 

  16. Hoogerbrugge PM, Poorthuis BJ, Romme AE, van de Kamp JJ, Wagemaker G, van Bekkum DW (1988) Effect of bone marrow transplantation on enzyme levels and clinical course in the neurologically affected twitcher mouse. J Clin Invest 81:1790–1794

    Article  PubMed  CAS  Google Scholar 

  17. Hoogerbrugge PM, Suzuki K, Suzuki K, Poorthuis BJ, Kobayashi T, Wagemaker G, van Bekkum DW (1988) Donor-derived cells in the central nervous system of twitcher mice after bone marrow transplantation. Science 239:1035–1038

    Article  PubMed  CAS  Google Scholar 

  18. Hoogerbrugge PM, Poorthuis BJ, Wagemaker G, van Bekkum DW, Suzuki K (1989) Alleviation of neurologic symptoms after bone marrow transplantation in Twitcher mice. Transplant Proc 21:2980–2981

    PubMed  CAS  Google Scholar 

  19. Luzi P, Rafi MA, Zaka M, Rao HZ, Curtis M, Vanier MT, Wenger DA (2005) Biochemical and pathological evaluation of long-lived mice with globoid cell leukodystrophy after bone marrow transplantation. Mol Genet Metab 86:150–159

    Article  PubMed  CAS  Google Scholar 

  20. Wu YP, McMahon E, Kraine MR, Tisch R, Meyers A, Frelinger J, Matsushima GK, Suzuki K (2000) Distribution and characterization of GFP(+) donor hematogenous cells in Twitcher mice after bone marrow transplantation. Am J Pathol 156:1849–1854

    PubMed  CAS  Google Scholar 

  21. Wu YP, McMahon EJ, Matsuda J, Suzuki K, Matsushima GK, Suzuki K (2001) Expression of immune-related molecules is downregulated in twitcher mice following bone marrow transplantation. J Neuropathol Exp Neurol 60:1062–1074

    PubMed  CAS  Google Scholar 

  22. Yagi T, McMahon EJ, Takikita S, Mohri I, Matsushima GK, Suzuki K (2004) Fate of donor hematopoietic cells in demyelinating mutant mouse, twitcher, following transplantation of GFP+ bone marrow cells. Neurobiol Dis 16:98–109

    Article  PubMed  Google Scholar 

  23. Fukuda A, Fukuda H, Jonsson M, Swanpalmer J, Hertzman S, Lannering B, Bjork-Eriksson T, Marky I, Blomgren K (2005) Progenitor cell injury after irradiation to the developing brain can be modulated by mild hypothermia or hyperthermia. J Neurochem 94:1604–1619

    Article  PubMed  CAS  Google Scholar 

  24. Fukuda A, Fukuda H, Swanpalmer J, Hertzman S, Lannering B, Marky I, Bjork-Eriksson T, Blomgren K (2005) Age-dependent sensitivity of the developing brain to irradiation is correlated with the number and vulnerability of progenitor cells. J Neurochem 92:569–584

    Article  PubMed  CAS  Google Scholar 

  25. Monje ML, Mizumatsu S, Fike JR, Palmer TD (2002) Irradiation induces neural precursor-cell dysfunction. Nat Med 8:955–962

    Article  PubMed  CAS  Google Scholar 

  26. Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR (2003) Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res 63:4021–4027

    PubMed  CAS  Google Scholar 

  27. Doetsch F, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Regeneration of a germinal layer in the adult mammalian brain. Proc Natl Acad Sci U S A 96:11619–24

    Article  PubMed  CAS  Google Scholar 

  28. Seri B, Garcia-Verdugo JM, Collado-Morente L, McEwen BS, Alvarez-Buylla A (2004) Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus. J Comp Neurol 478:359–378

    Article  PubMed  Google Scholar 

  29. Quinones-Hinojosa A, Sanai N, Soriano-Navarro M, Gonzalez-Perez O, Mirzadeh Z, Gil-Perotin S, Romero-Rodriguez R, Berger MS, Garcia-Verdugo JM, Alvarez-Buylla A (2006) Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells. J Comp Neurol 494:415–434

    Article  PubMed  Google Scholar 

  30. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970

    Article  PubMed  CAS  Google Scholar 

  31. Goings GE, Sahni V, Szele FG (2004) Migration patterns of subventricular zone cells in adult mice change after cerebral cortex injury. Brain Res 996:213–226

    Article  PubMed  CAS  Google Scholar 

  32. Sakai N, Inui K, Tatsumi N, Fukushima H, Nishigaki T, Taniike M, Nishimoto J, Tsukamoto H, Yanagihara I, Ozono K, Okada S (1996) Molecular cloning and expression of cDNA for murine galactocerebrosidase and mutation analysis of the twitcher mouse, a model of Krabbe’s disease. J Neurochem 66:1118–1124

    Article  PubMed  CAS  Google Scholar 

  33. Givogri MI, Galbiati F, Fasano S, Amadio S, Perani L, Superchi D, Morana P, Del Carro U, Marchesini S, Brambilla R, Wrabetz L, Bongarzone E (2006) Oligodendroglial progenitor cell therapy limits central neurological deficits in mice with metachromatic leukodystrophy. J Neurosci 26:3109–3119

    Article  PubMed  CAS  Google Scholar 

  34. Croci C, Fasano S, Superchi D, Perani L, Martellosio A, Brambilla R, Consalez G, Bongarzone ER (2006) Cerebellar neurons and glial cells are transducible by lentiviral vectors without decrease of cerebellar functions. Dev Neurosci 28:216–221

    Article  PubMed  CAS  Google Scholar 

  35. Suzuki K, Hoogerbrugge PM, Poorthuis BJ, Bekkum DW, Suzuki K (1998) The twitcher mouse. Central nervous system pathology after bone marrow transplantation. Lab Invest 58:302–309

    Google Scholar 

  36. Kondo A, Hoogerbrugge PM, Suzuki K, Poorthuis BJ, Van Bekkum DW, Suzuki K (1988) Pathology of the peripheral nerve in the twitcher mouse following bone marrow transplantation. Brain Res 460:178–183

    Article  PubMed  CAS  Google Scholar 

  37. Amano T, Inamura T, Wu CM, Kura S, Nakamizo A, Inoha S, Miyazono M, Ikezaki K (2002) Effects of single low dose irradiation on subventricular zone cells in juvenile rat brain. Neurol Res 24:809–816

    Article  PubMed  Google Scholar 

  38. Chiang CS, Mason KA, Withers HR, McBride WH (1992) Alteration in myelin-associated proteins following spinal cord irradiation in guinea pigs. Int J Radiat Oncol Biol Phys 24:929–937

    PubMed  CAS  Google Scholar 

  39. Lawson LJ, Perry VH, Gordon S (1992) Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48:405–415

    Article  PubMed  CAS  Google Scholar 

  40. Givogri MI, de Planell M, Galbiati F, Superchi D, Gritti A, Vescovi A, de Vellis J, Bongarzone ER (2006) Notch signaling in astrocytes and neuroblasts of the adult subventricular zone in health and after cortical injury. Dev Neurosci 28:81–91

    Article  PubMed  CAS  Google Scholar 

  41. Felling RJ, Snyder MJ, Romanko MJ, Rothstein RP, Ziegler AN, Yang Z, Givogri MI, Bongarzone ER, Levison SW (2006) Neural stem/progenitor cells participate in the regenerative response to perinatal hypoxia/ischemia. J Neurosci 26:4359–4369

    Article  PubMed  CAS  Google Scholar 

  42. Sato G, Tanaka R, Akiyama K, Yamanaka R, Sato M (2003) Immunohistochemical analysis of myelination following hemicranial irradiation in neonatal rats. Neurosci Lett 353:131–134

    Article  PubMed  CAS  Google Scholar 

  43. Lo Y, Taylor JM, McBride WH, Withers HR (1993) The effect of fractionated doses of radiation on mouse spinal cord. Int J Radiat Oncol Biol Phys 27:309–317

    PubMed  CAS  Google Scholar 

  44. Akassoglou K, Bauer J, Kassiotis G, Pasparakis M, Lassmann H, Kollias G, Probert L (1998) Oligodendrocytes apoptosis and primary demyelination induced by local TNF/p55TNFR signaling in the central nervous system of trangenic mice. Am J Pathol 153:801–812

    PubMed  CAS  Google Scholar 

  45. Hovelmeyer N, Hao Z, Kranidioti K, Kassiotis G, Buch T, Frommer F, von Hoch L, Kramer D, Minichiello L, Kollias G, Lassmann H, Waisman A (2005) Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis. J Immunol 175:5875–5884

    PubMed  Google Scholar 

  46. Jurewicz A, Matysiak M, Tybor K, Kilianek L, Raine CS, Selmaj K (2005) Tumour necrosis factor-induced death of adult human oligodendrocytes is mediated by apoptosis inducing factor. Brain 128:2675–2688

    Article  PubMed  Google Scholar 

  47. Pang Y, Cai Z, Rhodes PG (2005) Effect of tumor necrosis factor-alpha on developing optic nerve oligodendrocytes in culture. J Neurosci Res 80:226–234

    Article  PubMed  CAS  Google Scholar 

  48. Ensoli F, Fiorelli V, Muratori DS, De Cristofaro M, Vincenzi L, Topino S, Novi A, Luzi G, Sirianni MC (1999) Immune-derived cytokines in the nervous system: epigenetic instructive signals or neuropathogenic mediators? Crit Rev Immunol 19:97–116

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Maria Grazia Roncarolo for the generous contributions. This study was supported with grants from the Italian Telethon and the Italian Institutes of Health to ERB.

Author information

Author notes

  1. Maria I. Givogri & Ernesto R. Bongarzone

    Present address: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois, 808 South Wood Street. MC512, Chicago, IL, 60612, USA

Authors and Affiliations

  1. San Raffaele Scientific Institute, Via Olgettina 58, Milano, 20132, Italy

    Francesca Galbiati, Giulia Clementi, Daniela Superchi, Maria I. Givogri & Ernesto R. Bongarzone

Authors
  1. Francesca Galbiati
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giulia Clementi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniela Superchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria I. Givogri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ernesto R. Bongarzone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ernesto R. Bongarzone.

Additional information

Special Issue dedicated to Tony and Celia Campagnoni.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Galbiati, F., Clementi, G., Superchi, D. et al. Effects of Irradiation on the Postnatal Development of the Brain in a Genetic Mouse Model of Globoid Cell Leukodystrophy. Neurochem Res 32, 377–388 (2007). https://doi.org/10.1007/s11064-006-9247-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-006-9247-z

Keywords

Search

Navigation