Mutations in gigaxonin 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 TBCB. Here, we report the generation of a mouse model with targeted deletion of Gan exon 1 (GanΔexon1;Δexon1). Analyses of the GanΔexon1;Δexon1 mice revealed increased levels of various IFs proteins in nervous system and the presence of IFs inclusion bodies in the brain. Despite deficiency of full length gigaxonin, the GanΔexon1;Δexon1 mice do not develop overt neurological phenotypes and giant axons reminiscent of the human GAN disease. We propose that the existence of a short gigaxonin isoform expressed in the spinal cord could underlie the mitigation of GAN-phenotypes in GanΔexon1;Δexon1 mice. Nonetheless, the GanΔexon1;Δexon1 mice exhibited modest increase in axon calibers and 27% axonal loss in the L5 ventral roots. This new mouse model should provide a useful tool for testing potential therapeutic approaches for GAN disease.

An increase in the expression of the proinflammatory cytokine tumor necrosis factor ␣ (TNF-␣) has been observed in patients with amyotrophic lateral sclerosis (ALS) and in the mice models of the disease. TNF-␣ is a potent activator of macrophages and microglia and, under certain conditions, can induce or exacerbate neuronal cell death. Here, we assessed the contribution of TNF-␣ in motor neuron disease in mice overexpressing mutant superoxide dismutase 1 (SOD1) genes linked to familial ALS. This was accomplished by the generation of mice expressing SOD1 G37R or SOD1 G93A mutants in the context of TNF-␣ gene knock out. Surprisingly, the absence of TNF-␣ did not affect the lifespan or the extent of motor neuron loss in SOD1 transgenic mice. These results provide compelling evidence indicating that TNF-␣ does not directly contribute to motor neuron degeneration caused by SOD1 mutations.

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Mutations in the gene encoding for the neurofilament light subunit (NF-L) are responsible for Charcot-Marie-Tooth (CMT) neuropathy type 2E. To address whether CMT2E disease is potentially reversible, we generated a mouse model with conditional doxycycline-responsive gene system that allows repression of mutant hNF-LP22S transgene expression in adult neurons. The hNF-LP22S;tTa transgenic (tg) mice recapitulated key features of CMT2E disease, including aberrant hindlimb posture, motor deficits, hypertrophy of muscle fibres and loss of muscle innervation without neuronal loss. Remarkably, a 3-month treatment of hNF-LP22S;tTa mice with doxycycline after onset of disease efficiently down-regulated expression of hNF-LP22S and it caused reversal of CMT neurological phenotypes with restoration of muscle innervation and of neurofilament protein distribution along the sciatic nerve. These data suggest that therapeutic approaches aimed at abolishing expression or neutralizing hNF-L mutants might not only halt the progress of CMT2E disease, but also revert the disabilities.