title: Modest loss of peripheral axons, muscle atrophy and formation of brain inclusions in mice with targeted deletion of gigaxonin exon 1.
abstract: Mutations in the gigaxonin gene are responsible for giant axonal neuropathy (GAN), a progressive neurodegenerative disorder associated with abnormal accumulations of Intermediate Filaments (IFs). Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. Here, we report the generation of a mouse model with targeted deletion of Gan exon 1 (Gan(Deltaexon1;Deltaexon1)). Analyses of the Gan(Deltaexon1;Deltaexon1) mice revealed increased levels of various IFs proteins in the nervous system and the presence of IFs inclusion bodies in the brain. Despite deficiency of full length gigaxonin, the Gan(Deltaexon1;Deltaexon1) mice do not develop overt neurological phenotypes and giant axons reminiscent of the human GAN disease. Nonetheless, at 6 months of age the Gan(Deltaexon1;Deltaexon1) mice exhibit a modest hind limb muscle atrophy, a 10% decrease of muscle innervation and a 27% axonal loss in the L5 ventral roots. This new mouse model should provide a useful tool to test potential therapeutic approaches for GAN disease.
authors.affiliation: CHUL Research Centre and Department of Anatomy and Physiology, Laval University, Québec City, Québec, Canada.
authors.forename: Florence
authors.initials: F
authors.lastname: Dequen
authors.forename: Pascale
authors.initials: P
authors.lastname: Bomont
authors.forename: Geneviève
authors.initials: G
authors.lastname: Gowing
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells; D005091:Exons / Q000235:genetics; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018390:Gene Targeting / Q000379:methods; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000294:innervation / Q000503:physiopathology; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010641:Phenotype; D013126:Spinal Nerve Roots / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014855:Wallerian Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D003598:Cytoskeletal Proteins; C501171:Gan protein, mouse; D007381:Intermediate Filament Proteins; D008869:Microtubule-Associated Proteins