Modest loss of peripheral axons, muscle atrophy and formation of brain inclusions in mice with targeted deletion of gigaxonin exon 1

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.