title: 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.
authors.affiliation: Research Centre of CHUQ, Department of Psychiatry and Neurosciences, Laval University, Québec, Canada.
authors.forename: Florence
authors.initials: F
authors.lastname: Dequen
authors.forename: Mohammed
authors.initials: M
authors.lastname: Filali
authors.forename: Roxanne C
authors.initials: RC
authors.lastname: Larivière
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Perrot
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Hisanaga
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D015536:Down-Regulation; D051379:Mice; D008815:Mice, Inbred Strains; D009132:Muscles / Q000294:innervation / Q000473:pathology; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016900:Neurofilament Proteins / Q000235:genetics* / Q000378:metabolism; D012584:Sciatic Nerve / Q000473:pathology
chemical_list: D050505:Mutant Proteins; D016900:Neurofilament Proteins