Mutations in neurofilament light (NF-L) have been linked to Charcot–Marie–Tooth disease type 2E (CMT2E) in humans. To provide insight into disease pathogenesis, we developed a novel line of CMT2E mice that constitutively express human NF-L (hNF-L) with a glutamic acid to lysine mutation at position 397 (hNF-LE397K). This new line of mice developed signs consistent with CMT2E patients. Disease signs were first observed at 4 months in hNF-LE397K mice, and consisted of aberrant hind limb posture, digit deformities, reduced voluntary locomotor activity, reduced motor nerve conduction velocities (MNCVs) and muscle atrophy. Reduced voluntary locomotor activity and muscle pathology occurred without significant denervation, and hNF-LE397K mice showed relatively mild signs of nerve pathology. Nerve pathology in hNF-LE397K mice was characterized by ectopic accumulations of phosphorylated NFs in motor neuron cell bodies as early as 1 month. Moreover, NF organization was altered in motor and sensory roots, with small motor axons being most affected. Peak axonal diameter was reduced for small motor axons prior to and after the onset of overt phenotypes, whereas large motor axons were affected only after onset, which correlated with reduced MNCVs. Additionally, there was a small reduction in the number of sensory axons in symptomatic hNF-LE397K mice. hNF-LE397K mice are a novel line of CMT2E mice that recapitulate many of the overt phenotypes observed in CMT2E patients and hNF-LP22S mice. The cellular pathology observed in hNF-LE397K mice differed from that recently reported in hNF-LP22S mice, suggesting that overt CMT2E phenotypes may arise through different cellular mechanisms.
Shen, Hailian; Barry, Devin M.; Dale, Jeffrey M.; Garcia, Virginia B.; Calcutt, Nigel A.; Garcia, Michael L.
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