title: Quantitative and integrative proteome analysis of peripheral nerve myelin identifies novel myelin proteins and candidate neuropathy loci.
abstract: Peripheral nerve myelin facilitates rapid impulse conduction and normal motor and sensory functions. Many aspects of myelin biogenesis, glia-axonal interactions, and nerve homeostasis are poorly understood at the molecular level. We therefore hypothesized that only a fraction of all relevant myelin proteins has been identified so far. Combining gel-based and gel-free proteomic approaches, we identified 545 proteins in purified mouse sciatic nerve myelin, including 36 previously known myelin constituents. By mass spectrometric quantification, the predominant P0, periaxin, and myelin basic protein constitute 21, 16, and 8% of the total myelin protein, respectively, suggesting that their relative abundance was previously misestimated due to technical limitations regarding protein separation and visualization. Focusing on tetraspan-transmembrane proteins, we validated novel myelin constituents using immuno-based methods. Bioinformatic comparison with mRNA-abundance profiles allowed the categorization in functional groups coregulated during myelin biogenesis and maturation. By differential myelin proteome analysis, we found that the abundance of septin 9, the protein affected in hereditary neuralgic amyotrophy, is strongly increased in a novel mouse model of demyelinating neuropathy caused by the loss of prion protein. Finally, the systematic comparison of our compendium with the positions of human disease loci allowed us to identify several candidate genes for hereditary demyelinating neuropathies. These results illustrate how the integration of unbiased proteome, transcriptome, and genome data can contribute to a molecular dissection of the biogenesis, cell biology, metabolism, and pathology of myelin.
authors.affiliation: Department of Neurogenetics, and Proteomics Group, Max Planck Institute of Experimental Medicine, D-37075 Göttingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Patzig
authors.forename: Olaf
authors.initials: O
authors.lastname: Jahn
authors.forename: Stefan
authors.initials: S
authors.lastname: Tenzer
authors.forename: Sven P
authors.initials: SP
authors.lastname: Wichert
authors.forename: Patricia
authors.initials: P
authors.lastname: de Monasterio-Schrader
authors.forename: Susanne
authors.initials: S
authors.lastname: Rosfa
authors.forename: Jörg
authors.initials: J
authors.lastname: Kuharev
authors.forename: Kuo
authors.initials: K
authors.lastname: Yan
authors.forename: Ingo
authors.initials: I
authors.lastname: Bormuth
authors.forename: Juliane
authors.initials: J
authors.lastname: Bremer
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
authors.forename: Foteini
authors.initials: F
authors.lastname: Orfaniotou
authors.forename: Dörte
authors.initials: D
authors.lastname: Hesse
authors.forename: Markus H
authors.initials: MH
authors.lastname: Schwab
authors.forename: Wiebke
authors.initials: W
authors.lastname: Möbius
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.forename: Hauke Bernhard
authors.initials: HB
authors.lastname: Werner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018925:Chemokines / Q000032:analysis / Q000378:metabolism; D019295:Computational Biology; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015180:Electrophoresis, Gel, Two-Dimensional; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008970:Molecular Weight; D009185:Myelin Proteins / Q000032:analysis* / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000737:chemistry / Q000378:metabolism*; D011328:Prions / Q000235:genetics; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D012333:RNA, Messenger; D012584:Sciatic Nerve / Q000033:anatomy & histology* / Q000378:metabolism; D058112:Septins / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D060185:Tetraspanin 24 / Q000032:analysis / Q000378:metabolism
chemical_list: C554716:Cd151 protein, mouse; D018925:Chemokines; D008565:Membrane Proteins; D009185:Myelin Proteins; D011328:Prions; D020543:Proteome; D012333:RNA, Messenger; D060185:Tetraspanin 24; D058112:Septins
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