Résumé
The nervous system evolved a variety of connections and neuron types to sustain diverse functions. While challenging, unlocking the universal mechanisms that support neuron integrity can be addressed in giant axonal neuropathy (GAN), a rare and fatal disease with broad deterioration of the nervous system. Here, we describe a new mouse strain that recapitulates key aspects of the GAN pathology following the introduction of a disease-causing mutation in GAN. Unlike previous GAN knock-out mice which show no overt phenotype, GAN
mice exhibit early sensory-motor deficits and ataxia, giant axons and demyelination which, together with increased abundance, dramatic compaction and disorganization of neurofilaments across the nervous system, mimics the human disease. Using this model, we uncover novel alterations within neuromuscular junctions and muscles that might contribute to GAN pathogenesis. Interestingly, we pinpoint a sex bias whereby females show more severe histopathological damage and disease severity. Altogether, the GAN
strain provides the first robust rodent model for GAN, recapitulating the symptoms and histological hallmarks of the human pathology. This model will be invaluable when investigating the cellular and molecular mechanisms that uphold neuron integrity along with effective therapies for GAN.