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

International audienceABSTRACT: 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

Space and time scaling issues in data management: the virtual restitution of Cluniac heritage

Recent research projects led in Cluny have focused on interoperability issues between computer-aided design (CAD) and geographic information system (GIS). In one of these projects, the Gunzo project went through a complete digital restitution of what was the largest church in the world during five centuries. In another project, a 3D GIS of the Cluny region was set up and led to the idea of designing an online historical and archaeological 3D database. This involves the development of time-based 3D data management functionalities in which both CAD and GIS could exchange information. Thanks to the close collaboration between interdisciplinary fields, the team managed to formulate the basis of a joint workflow. These steps are promising and could meet in the future this long-time dream of the scientific community: to be able to tie together CAD and GIS models with temporality on a single georeferenced collaborative platform, so closely that it will be possible to navigate through the history of a city in 3D.Conseil Régional de Bourgogne, FEDER, ENSAM, Conseil Général de Saône et Loir

Rôle protecteur de certaines peintures rupestres du Soudan français

de Ganay Solange. Rôle protecteur de certaines peintures rupestres du Soudan français. In: Journal de la Société des Africanistes, 1940, tome 10. pp. 87-98

Caractérisation du modèle murin de la Neuropathie à Axones Géants : rôle de la gigaxonine dans la survie neuronale et l'organisation du cytosquelette

La Neuropathie à Axones Géants (NAG) est une maladie neurodégénérative rare et fatale caractérisée par une détérioration du système nerveux central et périphérique, impliquant les fonctions motrices et sensorielles. La détérioration massive du système nerveux est accompagnée d'une désorganisation générale des Filaments Intermédiaires ce qui la différencie de nombreuses maladies neurodégénératives où seuls les neurofilaments(NFs) sont affectés. La protéine déficiente, la gigaxonine, est la sous-unité d'une ubiquitine ligase E3, responsable de la reconnaissance spécifique des substrats MAP1B, MAP1S et TBCB, seuls connus à ce jour.Dans le but d'étudier le rôle de la gigaxonine sur la survie neuronale, la désorganisation du cytosquelette et d'avoir un modèle animal suffisamment fort pour envisager des tests thérapeutiques, j'ai caractérisé un modèle murin de NAG. Pour ce faire, j'ai réalisé une étude comportementale des fonctions motrices et sensorielles ainsi qu'une étude histopathologique. Les souris NAG (129/SvJ) développent un phénotype moteur modéré dès 60 semaines alors que les souris NAG (C57BL/6) présentent un phénotype sensoriel dès 60 semaines. Les données histopathologiques ne présentent pas de mort neuronale mais les NFs sont sévèrement altérés. Les NFs sont plus abondant, leur diamètre est augmenté et leur orientation hétérogène, comme c'est observé chez les patients NAG.Nos résultats montrent que l'absence de gigaxonine induit un phénotype moteur et sensoriel modéré mais par contre reproduit la désorganisation massive des NFs observée chez les patients. Ce modèle va nous permettred'étudier le rôle de la gigaxonine, une ligase E3, sur l'organisation des NFs et ainsi comprendre les processus pathologiques impliqués dans d'autres maladies neurodégénératives caractérisée par une accumulation des NFs et un dysfonctionnement du système ubiquitine-protéasome comme les maladies d'Azheimer, de Parkinson etd'huntington ou la sclérose latérale amyotrophique.Giant Axonal Neuropathy (GAN) is a rare and fatale neurodegenerative disorder characterized by a deterioration of the peripheral and central nervous system. The broad deterioration of the nervous system is accompanied with a general disorganization of the Intermediate Filaments which makes it different from other neurodegenerative disorders wherein only neurofilaments (NFs) are affected. The defective protein, gigaxonin, is the substrate adaptator of an E3 ubiquitin ligase, in charge of the specific recognition of MAP1B, MAP1S and TBCB. In order to study the role of gigaxonin on neuronal survival, the cytoskeleton disorganization and to have a relevant GAN animal model to evaluate efficacy of GAN treatments, I have characterized a GAN mouse model. I did a motor and sensory behavioural study and an histopathologic study. The GAN mice (129/SvJ) shown mild motordeficits starting at 60 weeks of age while sensory deficits were evidenced in C57BL/6 GAN mice. No apparent neurodegeneration was evidenced in GAN mice, but dysregulation of NFs was massive. NFs were more abundant, they shown the abnormal increased diameter and misorientation that are characteristics of the human pathology. Our results show that gigaxonin depletion induces mild motor and sensory deficits but recapitulates the severe NFs dysregulation seen in patients. Our model will allow us to study the role of the gigaxonin-E3 ligase in organizing NFs and understand the pathological processes engaged in other neurodegenerative disorders characterized by accumulation of NFs and dysfunction of the Ubiquitin Proteasome System, such as Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's and Parkinson's diseases

Le xylophone chez les Sara du Moyen Chari

de Ganay Solange. Le xylophone chez les Sara du Moyen Chari. In: Journal de la Société des Africanistes, 1942, tome 12. pp. 203-240

Note sur le culte du lebe chez les Dogon du Soudan français

de Ganay Solange. Note sur le culte du lebe chez les Dogon du Soudan français. In: Journal de la Société des Africanistes, 1937, tome 7, fascicule 2. pp. 203-211

Une statuette d'ancêtre

de Ganay Solange. Une statuette d'ancêtre. In: Journal des africanistes, 1984, tome 54, fascicule 1. pp. 121-124

Sylvain, Grébaut, Catalogue des Manuscrits Éthiopiens de la Collection Griaule

de Ganay Solange. Sylvain, Grébaut, Catalogue des Manuscrits Éthiopiens de la Collection Griaule. In: Journal de la Société des Africanistes, 1940, tome 10. p. 197

Un jardin d'essai et son autel chez les Bambara

de Ganay Solange. Un jardin d'essai et son autel chez les Bambara. In: Journal de la Société des Africanistes, 1947, tome 17. pp. 57-63