title: An essential role of MAG in mediating axon-myelin attachment in Charcot-Marie-Tooth 1A disease.
abstract: Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary demyelinating peripheral neuropathy caused by the duplication of the PMP22 gene. Demyelination precedes the occurrence of clinical symptoms that correlate with axonal degeneration. It was postulated that a disturbed axon-glia interface contributes to altered myelination consequently leading to axonal degeneration. In this study, we examined the expression of MAG and Necl4, two critical adhesion molecules that are present at the axon-glia interface, in sural nerve biopsies of CMT1A patients and in peripheral nerves of mice overexpressing human PMP22, an animal model for CMT1A. We show an increase in the expression of MAG and a strong decrease of Necl4 in biopsies of CMT1A patients as well as in CMT1A mice. Expression analysis revealed that MAG is strongly upregulated during peripheral nerve maturation, whereas Necl4 expression remains very low. Ablating MAG in CMT1A mice results in separation of axons from their myelin sheath. Our data show that MAG is important for axon-glia contact in a model for CMT1A, and suggest that its increased expression in CMT1A disease has a compensatory role in the pathology of the disease. Thus, we demonstrate that MAG together with other adhesion molecules such as Necl4 is important in sustaining axonal integrity.
authors.affiliation: Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. Electronic address: j.kinter@unibas.ch.
authors.forename: Jochen
authors.initials: J
authors.lastname: Kinter
authors.affiliation: Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. Electronic address: thomas.lazzati@unibas.ch.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lazzati
authors.affiliation: Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. Electronic address: daniela.schmid@unibas.ch.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schmid
authors.affiliation: Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. Electronic address: thomas.zeis@unibas.ch.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zeis
authors.affiliation: Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. Electronic address: beat.erne@unibas.ch.
authors.forename: Beat
authors.initials: B
authors.lastname: Erne
authors.affiliation: Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland; Department of Neurology, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. Electronic address: roland.luetzelschwab@roche.com.
authors.forename: Roland
authors.initials: R
authors.lastname: Lützelschwab
authors.affiliation: Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland; Department of Neurology, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. Electronic address: asteck@uhbs.ch.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Steck
authors.affiliation: IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy. Electronic address: davide.pareyson@istituto-besta.it.
authors.forename: Davide
authors.initials: D
authors.lastname: Pareyson
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, POB 26, Rehovot 76100, Israel. Electronic address: peles@weizmann.ac.il.
authors.forename: Elior
authors.initials: E
authors.lastname: Peles
authors.affiliation: Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland; Department of Neurology, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. Electronic address: nicole.schaeren-wiemers@unibas.ch.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schaeren-Wiemers
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D018992:Myelin-Associated Glycoprotein / Q000235:genetics / Q000378:metabolism*; D013497:Sural Nerve / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: C498601:CADM4 protein, human; D015815:Cell Adhesion Molecules; C498602:Igsf4c protein, mouse; D007136:Immunoglobulins; C115082:MAG protein, human; C104739:Mag protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; C073687:PMP22 protein, human