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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Axons / metabolism
-
Axons / pathology
-
Brain / metabolism*
-
Brain / physiopathology
-
Cells, Cultured
-
Cytoskeletal Proteins / deficiency*
-
Cytoskeletal Proteins / genetics
-
Cytoskeletal Proteins / metabolism
-
Disease Models, Animal
-
Embryonic Stem Cells
-
Exons / genetics
-
Ganglia, Spinal / metabolism
-
Ganglia, Spinal / pathology
-
Ganglia, Spinal / physiopathology
-
Gene Targeting / methods
-
Inclusion Bodies / genetics
-
Inclusion Bodies / metabolism
-
Inclusion Bodies / pathology
-
Intermediate Filament Proteins / metabolism
-
Mice
-
Mice, Knockout
-
Microtubule-Associated Proteins / metabolism
-
Motor Neurons / metabolism
-
Motor Neurons / pathology
-
Muscle, Skeletal / innervation
-
Muscle, Skeletal / physiopathology
-
Muscular Atrophy / genetics
-
Muscular Atrophy / metabolism*
-
Muscular Atrophy / physiopathology
-
Neurodegenerative Diseases / genetics
-
Neurodegenerative Diseases / metabolism*
-
Neurodegenerative Diseases / physiopathology
-
Peripheral Nervous System Diseases / genetics
-
Peripheral Nervous System Diseases / metabolism*
-
Peripheral Nervous System Diseases / physiopathology
-
Phenotype
-
Spinal Nerve Roots / metabolism
-
Spinal Nerve Roots / pathology
-
Spinal Nerve Roots / physiopathology
-
Wallerian Degeneration / genetics
-
Wallerian Degeneration / metabolism*
-
Wallerian Degeneration / physiopathology
Substances
-
Cytoskeletal Proteins
-
Gan protein, mouse
-
Intermediate Filament Proteins
-
Microtubule-Associated Proteins