title: Proteolipid protein modulates preservation of peripheral axons and premature death when myelin protein zero is lacking.
abstract: Protein zero (P0) is the major structural component of peripheral myelin. Lack of this adhesion protein from Schwann cells causes a severe dysmyelinating neuropathy with secondary axonal degeneration in humans with the neuropathy Dejerine-Sottas syndrome (DSS) and in the corresponding mouse model (P0(null)-mice). In the mammalian CNS, the tetraspan-membrane protein PLP is the major structural myelin constituent and required for the long-term preservation of myelinated axons, which fails in hereditary spastic paraplegia (SPG type-2) and the relevant mouse model (Plp(null)-mice). The Plp-gene is also expressed in Schwann cells but PLP is of very low abundance in normal peripheral myelin; its function has thus remained enigmatic. Here we show that the abundance of PLP but not of other tetraspan myelin proteins is strongly increased in compact peripheral myelin of P0(null)-mice. To determine the functional relevance of PLP expression in the absence of P0, we generated P0(null)*Plp(null)-double-mutant mice. Compared with either single-mutant, P0(null)*Plp(null)-mice display impaired nerve conduction, reduced motor functions, and premature death. At the morphological level, axonal segments were frequently non-myelinated but in a one-to-one relationship with a hypertrophic Schwann cell. Importantly, axonal numbers were reduced in the vital phrenic nerve of P0(null)*Plp(null)-mice. In the absence of P0, thus, PLP also contributes to myelination by Schwann cells and to the preservation of peripheral axons. These data provide a link between the Schwann cell-dependent support of peripheral axons and the oligodendrocyte-dependent support of central axons.
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Patzig
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kusch
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Fledrich
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Eichel
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Katja A
authors.initials: KA
authors.lastname: Lüders
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.|Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Möbius
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.|Department of Clinical Neurophysiology, University Medical Center, Göttingen, Germany.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sereda
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.affiliation: Department of Neurology, Developmental Neurobiology, University Hospital, Würzburg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Martini
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Hauke B
authors.initials: HB
authors.lastname: Werner
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D005260:Female; D053208:Kaplan-Meier Estimate; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061213:Mortality, Premature; D009043:Motor Activity / Q000502:physiology; D018993:Myelin P0 Protein / Q000235:genetics / Q000378:metabolism*; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009431:Neural Conduction / Q000502:physiology; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology; D010791:Phrenic Nerve / Q000378:metabolism* / Q000473:pathology; D012584:Sciatic Nerve / Q000378:metabolism* / Q000473:pathology
chemical_list: C104739:Mag protein, mouse; C560546:Mpz protein, mouse; D018993:Myelin P0 Protein; D018991:Myelin Proteolipid Protein; D018992:Myelin-Associated Glycoprotein; C047516:Plp1 protein, mouse
keywords: Charcot-Marie-tooth disease; Dejerine-Sottas syndrome; Schwann cell; glia-axonal support; hereditary spastic paraplegia (SPG-2); myelin; neurodegeneration; neuropathy; oligodendrocyte