Reversal of neuropathy phenotypes in conditional mouse model of Charcot–Marie–Tooth disease type 2E

Abstract

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.

Neurofilament Phosphorylation during Development and Disease: Which Came First, the Phosphorylation or the Accumulation?

“…Based on the previously described role of NF phosphorylation, abolished N-terminal phosphorylation would result in ectopic NF assembly and phosphorylation [7, 8, 75], altered NF transport [21, 26, 30, 33, 35], and ectopic NF accumulations [7, 8, 75]. Consistent with this prediction, transgenic mice expressing the CMT-linked head domain mutation, hNF-L P22S , displayed disrupted axonal transport [76]. Furthermore, mutations within a conserved sequence at the end of the rod domain, hNF-L E397K , also resulted in ectopic NF phosphorylation as early as 1 month [77].…”

Neural and Molecular Features on Charcot-Marie-Tooth Disease Plasticity and Therapy

“…A conditional mouse model, carrying the P22S mutation, mimics many aspects of the human CMT2E disease, including motor disability, abnormal muscle morphology, and denervation events [54]. These results highlight the importance of the integrity of the neurofilament network for neuronal function and suggest that the disease symptoms caused by the NEFL P 22 S mutation might result from axonal transport defects rather than deleterious effects of large neurofilament aggregates.…”

Neurofilamentopathy in Neurodegenerative Diseases

“…The role of neurofilaments was further clarified by using double transgenic mice, hNF-L P22S ; that model CMT2E [70]. They suggest CMT pathology is mostly unrelated to the NF accumulation in the cell bodies, as they found normal NF density in axons but instead decreased density of microtubules.…”