title: The Wlds transgene reduces axon loss in a Charcot-Marie-Tooth disease 1A rat model and nicotinamide delays post-traumatic axonal degeneration.
abstract: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and a duplication of the peripheral myelin protein of 22 kDa (PMP22) gene causes the most frequent subform CMT1A. Clinical impairments are determined by the amount of axonal loss. Axons of the spontaneous mouse mutant Wallerian degeneration slow (Wlds) show markedly reduced degeneration following various types of injuries. Protection is conferred by a chimeric Wlds gene encoding an N-terminal part of ubiquitination factor Ube4b and full length nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1). Nmnat1 enzyme generates nicotinamide adenine dinucleotide (NAD) from nicotinamide mononucleotide. Here, in a Pmp22 transgenic animal model of Charcot-Marie-Tooth disease type 1A (CMT rat), the Wlds transgene reduced axonal loss and clinical impairments without altering demyelination. Furthermore, nicotinamide - substrate precursor of the Nmnat1 enzyme - transiently delayed posttraumatic axonal degeneration in an in vivo model of acute peripheral nerve injury, but to a lower extent than Wlds. In contrast, 8 weeks of nicotinamide treatment did not influence axonal loss or clinical manifestations in the CMT rat. Therefore, nicotinamide can partially substitute for the protective Wlds effect in acute traumatic, but not in chronic secondary axonal injury. Future studies are needed to develop axon protective therapy in CMT1A which may be combined with therapeutic strategies aimed at downregulation of toxic PMP22 overexpression.
authors.affiliation: Department of Neurology, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Meyer zu Horste
authors.forename: Timo A
authors.initials: TA
authors.lastname: Miesbach
authors.forename: Johanna I
authors.initials: JI
authors.lastname: Muller
authors.forename: Robert
authors.initials: R
authors.lastname: Fledrich
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Stassart
authors.forename: Bernd C
authors.initials: BC
authors.lastname: Kieseier
authors.forename: Michael P
authors.initials: MP
authors.lastname: Coleman
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sereda
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009536:Niacinamide / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D020426:Sciatic Neuropathy / Q000150:complications / Q000235:genetics* / Q000473:pathology; D014855:Wallerian Degeneration / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*
chemical_list: D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C533642:Wld protein, rat; D009536:Niacinamide