Sensory-motor deficits and Neurofilament disorganization in Gigaxonin-null mice. - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue Molecular Neurodegeneration Année : 2011

Sensory-motor deficits and Neurofilament disorganization in Gigaxonin-null mice.

Résumé

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 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.
Fichier principal
Vignette du fichier
1750-1326-6-25.pdf (4.33 Mo) Télécharger le fichier
1750-1326-6-25-S1.TIFF (2.63 Mo) Télécharger le fichier
1750-1326-6-25-S2.TIFF (3.63 Mo) Télécharger le fichier
1750-1326-6-25-S3.TIFF (2.84 Mo) Télécharger le fichier
1750-1326-6-25.xml (70.03 Ko) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte
Format : Autre
Format : Autre
Format : Autre
Format : Autre
Loading...

Dates et versions

inserm-00593292 , version 1 (13-05-2011)

Identifiants

Citer

Thibault Ganay, Alexia Boizot, Renaud Burrer, Jean Paul Chauvin, Pascale Bomont. Sensory-motor deficits and Neurofilament disorganization in Gigaxonin-null mice.. Molecular Neurodegeneration, 2011, 6 (1), pp.25. ⟨10.1186/1750-1326-6-25⟩. ⟨inserm-00593292⟩
159 Consultations
194 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More