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Acta Neuropathologica

, Volume 122, Issue 1, pp 35–48 | Cite as

Axonopathy is a compounding factor in the pathogenesis of Krabbe disease

  • Ludovico Cantuti Castelvetri
  • Maria Irene Givogri
  • Hongling Zhu
  • Benjamin Smith
  • Aurora Lopez-Rosas
  • Xi Qiu
  • Richard van Breemen
  • Ernesto Roque BongarzoneEmail author
Original Paper

Abstract

Loss-of-function of the lysosomal enzyme galactosyl-ceramidase causes the accumulation of the lipid raft-associated sphingolipid psychosine, the disruption of postnatal myelination, neurodegeneration and early death in most cases of infantile Krabbe disease. This work presents a first study towards understanding the progression of axonal defects in this disease using the Twitcher mutant mouse. Axonal swellings were detected in axons within the mutant spinal cord as early as 1 week after birth. As the disease progressed, more axonopathic profiles were found in other regions of the nervous system, including peripheral nerves and various brain areas. Isolated mutant neurons recapitulated axonal and neuronal defects in the absence of mutant myelinating glia, suggesting an autonomous neuronal defect. Psychosine was sufficient to induce axonal defects and cell death in cultures of acutely isolated neurons. Interestingly, axonopathy in young Twitcher mice occured in the absence of demyelination and of neuronal apoptosis. Neuronal damage occurred at later stages, when mutant mice were moribund and demyelinated. Altogether, these findings suggest a progressive dying-back neuronal dysfunction in Twitcher mutants.

Keywords

Leukodystrophies Twitcher Myelin Bone marrow Lentiviral vectors Dying-back pathology Axonal degeneration Axonal transport 

Notes

Acknowledgments

The authors wish to thank Scott Brady, Gerardo Morfini and Gustavo Pigino for discussions and the anonymous reviewers for their comments to improve the quality of this study. The authors dedicate this work to the memory of Nestore Cantuti Castelvetri. This study was partially funded by grants from NIH (RNS065808A), the Morton Cure paralysis foundation and the Board of Trustees at the University of Illinois to E.R.B.

Supplementary material

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ludovico Cantuti Castelvetri
    • 1
  • Maria Irene Givogri
    • 1
  • Hongling Zhu
    • 1
  • Benjamin Smith
    • 1
  • Aurora Lopez-Rosas
    • 1
  • Xi Qiu
    • 2
  • Richard van Breemen
    • 2
  • Ernesto Roque Bongarzone
    • 1
    Email author
  1. 1.Department of Anatomy and Cell BiologyCollege of Medicine, University of IllinoisChicagoUSA
  2. 2.Department of Medicinal Chemistry and PharmacognosyCollege of Pharmacy, University of IllinoisChicagoUSA

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