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Ganay T, Boizot A, Burrer R, et al. Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice. Mol Neurodegener. 2011;6:25doi: 10.1186/1750-1326-6-25.
Ganay, T., Boizot, A., Burrer, R., Chauvin, J. P., & Bomont, P. (2011). Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice. Molecular neurodegeneration, 625. https://doi.org/10.1186/1750-1326-6-25
Ganay, Thibault, et al. "Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice." Molecular neurodegeneration vol. 6 (2011): 25. doi: https://doi.org/10.1186/1750-1326-6-25
Ganay T, Boizot A, Burrer R, Chauvin JP, Bomont P. Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice. Mol Neurodegener. 2011 Apr 12;6:25. doi: 10.1186/1750-1326-6-25. PMID: 21486449; PMCID: PMC3094382.
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Mol Neurodegener. 2011 Apr 12;6:25. doi: 10.1186/1750-1326-6-25.

Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice.

Molecular neurodegeneration

Thibault Ganay, Alexia Boizot, Renaud Burrer, Jean Paul Chauvin, Pascale Bomont

Affiliations

  1. Inserm Unité 901, Marseille, 13009, France. [email protected].

PMID: 21486449 PMCID: PMC3094382 DOI: 10.1186/1750-1326-6-25

Abstract

BACKGROUND: Giant Axonal Neuropathy (GAN) is a fatal neurodegenerative disorder with early onset characterized by a severe deterioration of the peripheral and central nervous system, involving both the motor and the sensory tracts and leading to ataxia, speech defect and intellectual disabilities. The broad deterioration of the nervous system is accompanied by a generalized disorganization of the intermediate filaments, including neurofilaments in neurons, but the implication of this defect in disease onset or progression remains unknown. The identification of gigaxonin, the substrate adaptor of an E3 ubiquitin ligase, as the defective protein in GAN allows us to now investigate the crucial role of the gigaxonin-E3 ligase in sustaining neuronal and intermediate filament integrity. To study the mechanisms controlled by gigaxonin in these processes and to provide a relevant model to test the therapeutic approaches under development for GAN, we generated a Gigaxonin-null mouse by gene targeting.

RESULTS: We investigated for the first time in Gigaxonin-null mice the deterioration of the motor and sensory functions over time as well as the spatial disorganization of neurofilaments. We showed that gigaxonin depletion in mice induces mild but persistent motor deficits starting at 60 weeks of age in the 129/SvJ-genetic background, while sensory deficits were demonstrated in C57BL/6 animals. In our hands, another gigaxonin-null mouse did not display the early and severe motor deficits reported previously. No apparent neurodegeneration was observed in our knock-out mice, but dysregulation of neurofilaments in proximal and distal axons was massive. Indeed, neurofilaments were not only more abundant but they also showed the abnormal increase in diameter and misorientation that are characteristics of the human pathology.

CONCLUSIONS: Together, our results show that gigaxonin depletion in mice induces mild motor and sensory deficits but recapitulates the severe neurofilament dysregulation seen in patients. Our model will allow investigation of the role of the gigaxonin-E3 ligase in organizing neurofilaments and may prove useful in understanding the pathological processes engaged in other neurodegenerative disorders characterized by accumulation of neurofilaments and dysfunction of the Ubiquitin Proteasome System, such as Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's and Parkinson's diseases.

References

  1. Nat Cell Biol. 2003 Nov;5(11):1001-7 - PubMed
  2. Neurology. 1981 Nov;31(11):1470-3 - PubMed
  3. J Neurobiol. 2004 Jan;58(1):131-48 - PubMed
  4. J Neurol Neurosurg Psychiatry. 2005 Jun;76(6):825-32 - PubMed
  5. Nat Genet. 2000 Nov;26(3):370-4 - PubMed
  6. J Neurocytol. 1988 Apr;17(2):197-208 - PubMed
  7. J Child Neurol. 1990 Jul;5(3):229-34 - PubMed
  8. Pediatrics. 1972 Jun;49(6):894-9 - PubMed
  9. Hum Mol Genet. 2009 Apr 15;18(8):1384-94 - PubMed
  10. Eur J Med Genet. 2008 Sep-Oct;51(5):426-35 - PubMed
  11. Brain Dev. 1989;11(4):207-14 - PubMed
  12. J Neurol Neurosurg Psychiatry. 2007 Nov;78(11):1267-70 - PubMed
  13. J Neurol Neurosurg Psychiatry. 1983 Jun;46(6):551-4 - PubMed
  14. Nature. 2003 Sep 18;425(6955):316-21 - PubMed
  15. Curr Biol. 2005 Nov 22;15(22):2050-5 - PubMed
  16. Nature. 2003 Sep 18;425(6955):311-6 - PubMed
  17. BMC Genet. 2007 Mar 01;8:6 - PubMed
  18. Acta Neuropathol. 1972;20(3):237-47 - PubMed
  19. Hum Mutat. 2003 Apr;21(4):446 - PubMed
  20. Exp Neurol. 1999 Jul;158(1):37-46 - PubMed
  21. Eur Neurol. 1991;31(1):50-6 - PubMed
  22. Nature. 1998 Apr 9;392(6676):605-8 - PubMed
  23. Hum Mol Genet. 2003 Apr 15;12(8):813-22 - PubMed
  24. Neuromuscul Disord. 2009 Apr;19(4):270-4 - PubMed
  25. Brain Res Bull. 2009 Oct 28;80(4-5):282-95 - PubMed
  26. Nature. 2005 Nov 10;438(7065):224-8 - PubMed
  27. Neuromuscul Disord. 2007 Aug;17(8):624-30 - PubMed
  28. Am J Med Genet A. 2010 Nov;152A(11):2802-4 - PubMed
  29. Neurology. 2002 Apr 23;58(8):1273-6 - PubMed
  30. Brain Dev. 1998 Dec;20(8):594-7 - PubMed
  31. J Child Neurol. 2009 Dec;24(12):1552-6 - PubMed
  32. Hum Mol Genet. 2006 May 1;15(9):1451-63 - PubMed
  33. J Neuropathol Exp Neurol. 1976 Jul;35(4):458-70 - PubMed
  34. Neurology. 2004 Jan 13;62(1):13-6 - PubMed
  35. J Neurochem. 2008 Oct;107(1):253-64 - PubMed

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