Skip to main content

Advertisement

SpringerLink
Log in

The Role of Peripheral Myelin Protein 2 in Remyelination

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The protein component of the myelin layer is essential for all aspects of peripheral nerves, and its deficiency can lead to structural and functional impairment. The presence of peripheral myelin protein 2 (P2, PMP2, FABP8, M-FABP) in Schwann cells has been known for decades and shown recently to be involved in the lipid homeostasis in the peripheral neural system. However, its precise role during de- and remyelination has yet to be elucidated. To this end, we assessed remyelination after sciatic nerve crush injury in vivo, and in an experimental de/remyelination ex vivo myelinating culture model in P2-deficient (P2 −/− ) and wild-type (WT) animals. In vivo, the nerve crush paradigm revealed temporal structural and functional changes in P2 −/− mice as compared to WT animals. Concomitantly, P2 −/− DRG cultures demonstrated the presence of shorter internodes and enlarged nodes after ex vivo de/remyelination. Together, these data indicate that P2 may play a role in remyelination of the injured peripheral nervous system, presumably by affecting the nodal and internodal configuration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

d:

Days

dML:

Distal motor latency

CMAP:

Maximum compound muscle action potential

CMT:

Charcot–Marie–Tooth

DRG:

Dorsal root ganglia

FABP:

Fatty acid binding protein

FKL:

Forskolin

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

MBP:

Myelin basic protein

MHC:

Major histocompatibility complex

NCV:

Nerve conduction velocity

P0:

Protein zero

P2:

Peripheral myelin protein 2

P2−/− :

P2-deficient

RT:

Room temperature

rtPCR:

Real-time polymerase chain reaction

SNCI:

Sciatic nerve crush injury

WT:

Wildtype

References

  • Bharucha VA, Peden KW, Subach BR, Narayanan V, Tennekoon GI (1993) Characterization of the cis-acting elements of the mouse myelin P2 promoter. J Neurosci Res 36:508–519

    Article  CAS  PubMed  Google Scholar 

  • Brown MC, Hardman VJ (1987) A reassessment of the accuracy of reinnervation by motoneurons following crushing or freezing of the sciatic or lumbar spinal nerves of rats. Brain 110(Pt 3):695–705

    Article  PubMed  Google Scholar 

  • Court FA et al (2004) Restricted growth of Schwann cells lacking Cajal bands slows conduction in myelinated nerves. Nature 431:191–195

    Article  CAS  PubMed  Google Scholar 

  • De Leon M, Welcher AA, Suter U, Shooter EM (1991) Identification of transcriptionally regulated genes after sciatic nerve injury. J Neurosci Res 29:437–448

    Article  PubMed  Google Scholar 

  • Dehmel T, Janke A, Hartung HP, Goebel HH, Wiendl H, Kieseier BC (2007) The cell-specific expression of metalloproteinase-disintegrins (ADAMs) in inflammatory myopathies. Neurobiol Dis 25:665–674. doi:10.1016/j.nbd.2006.11.008

    Article  CAS  PubMed  Google Scholar 

  • Gonzaga-Jauregui C et al (2015) Exome sequence analysis suggests that genetic burden contributes to phenotypic variability and complex. Neuropathy Cell Rep 12:1169–1183

    Article  CAS  PubMed  Google Scholar 

  • Greenfield S, Brostoff S, Eylar EH, Morell P (1973) Protein composition of myelin of the peripheral nervous system. J Neurochem 20:1207–1216

    Article  CAS  PubMed  Google Scholar 

  • Harauz G, Ladizhansky V, Boggs JM (2009) Structural polymorphism and multifunctionality of myelin basic protein. Biochemistry 48:8094–8104

    Article  CAS  PubMed  Google Scholar 

  • Hong YB et al (2016) A mutation in PMP2 causes dominant demyelinating Charcot-Marie-Tooth neuropathy. PLoS Genet 12:e1005829

    Article  PubMed  PubMed Central  Google Scholar 

  • Hughes RA et al (2008) Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet 7:136–144

    Article  CAS  PubMed  Google Scholar 

  • Inglis HR, Csurhes PA, McCombe PA (2007) Antibody responses to peptides of peripheral nerve myelin proteins P0 and P2 in patients with inflammatory demyelinating neuropathy. J Neurol Neurosurg Psychiatry 78:419–422

    Article  CAS  PubMed  Google Scholar 

  • Kadlubowski M, Hughes RA, Gregson NA (1984) Spontaneous and experimental neuritis and the distribution of the myelin protein P2 in the nervous system. J Neurochem 42:123–129

    Article  CAS  PubMed  Google Scholar 

  • Khalili-Shirazi A, Atkinson P, Gregson N, Hughes RA (1993) Antibody responses to P0 and P2 myelin proteins in Guillain-Barre syndrome and chronic idiopathic demyelinating polyradiculoneuropathy. J Neuroimmunol 46:245–251

    Article  CAS  PubMed  Google Scholar 

  • Kirschner DA, Ganser AL (1980) Compact myelin exists in the absence of basic protein in the shiverer mutant mouse. Nature 283:207–210

    Article  CAS  PubMed  Google Scholar 

  • Knoll W et al (2014) Structural and dynamical properties of reconstituted myelin sheaths in the presence of myelin proteins MBP and P2 studied by neutron scattering. Soft Matter 10:519–529

    Article  CAS  PubMed  Google Scholar 

  • Lehmann HC et al (2009) Matrix metalloproteinase-2 is involved in myelination of dorsal root ganglia neurons Glia 57:479–489 doi:10.1002/glia.20774

  • Lemke G, Axel R (1985) Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin. Cell 40:501–508

    Article  CAS  PubMed  Google Scholar 

  • Luft JH (1961) Improvements in epoxy resin embedding methods. J Biophys Biochem Cytol 9:409–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Majava V et al (2010) Structural and functional characterization of human peripheral nervous system myelin protein P2. PLoS ONE 5:e10300

    Article  PubMed  PubMed Central  Google Scholar 

  • Meyer zu Horste G et al (2010) Mouse Schwann cells activate MHC class I and II restricted T-cell responses, but require external peptide processing for MHC class II presentation. Neurobiol Dis 37:483–490. doi:10.1016/j.nbd.2009.11.006

    Article  PubMed  Google Scholar 

  • Meyer zu Horste G et al (2014) FoxP3+ regulatory T cells determine disease severity in rodent models of inflammatory neuropathies. PLoS ONE 9:e108756

    Article  PubMed  PubMed Central  Google Scholar 

  • Motley WW et al (2016) De novo PMP2 mutations in families with type 1 Charcot-Marie-Tooth disease. Brain 139:1649–1656

    Article  PubMed  PubMed Central  Google Scholar 

  • Rostami A, Brown MJ, Lisak RP, Sumner AJ, Zweiman B, Pleasure DE (1984) The role of myelin P2 protein in the production of experimental allergic neuritis. Ann Neurol 16:680–685

    Article  CAS  PubMed  Google Scholar 

  • Ruskamo S et al (2014) Atomic resolution view into the structure-function relationships of the human myelin peripheral membrane protein P2. Acta Crystallogr 70:165–176

    CAS  Google Scholar 

  • Samsam M, Frei R, Marziniak M, Martini R, Sommer C (2002) Impaired sensory function in heterozygous P0 knockout mice is associated with nodal changes in sensory nerves. J Neurosci Res 67:167–173

    Article  CAS  PubMed  Google Scholar 

  • Sanders FK, Whitteridge D (1946) Conduction velocity and myelin thickness in regenerating nerve fibres. J Physiol 105:152–174

    Article  PubMed Central  Google Scholar 

  • Saporta MA, Katona I, Lewis RA, Masse S, Shy ME, Li J (2009) Shortened internodal length of dermal myelinated nerve fibres in Charcot-Marie-Tooth disease type 1A. Brain 132:3263–3273

    Article  PubMed  PubMed Central  Google Scholar 

  • Sedzik J, Jastrzebski JP (2011) High-resolution structural model of porcine P2 myelin membrane protein with associated fatty acid ligand: fact or artifact? J Neurosci Res 89:909–920

    Article  CAS  PubMed  Google Scholar 

  • Stettner M, Dehmel T, Mausberg AK, Kohne A, Rose CR, Kieseier BC (2011) Levetiracetam exhibits protective properties on rat Schwann cells in vitro. J Peripher Nerv Syst 16:250–260

    Article  CAS  PubMed  Google Scholar 

  • Stettner M et al (2013a) Promoting myelination in an in vitro mouse model of the peripheral nervous system: the effect of wine ingredients [corrected]. PLoS ONE 8:e66079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stettner M et al (2013b) A reliable in vitro model for studying peripheral nerve myelination in mouse. J Neurosci Methods 214:69–79

    Article  PubMed  Google Scholar 

  • Stettner M et al (2014) Interleukin-17 impedes Schwann cell-mediated myelination. J Neuroinflamm 11:63

    Article  Google Scholar 

  • Suresh S, Wang C, Nanekar R, Kursula P, Edwardson JM (2010) Myelin basic protein and myelin protein 2 act synergistically to cause stacking of lipid bilayers. Biochemistry 49:3456–3463

    Article  CAS  PubMed  Google Scholar 

  • Trapp BD, McIntyre LJ, Quarles RH, Sternberger NH, Webster HD (1979) Immunocytochemical localization of rat peripheral nervous system myelin proteins: P2 protein is not a component of all peripheral nervous system myelin sheaths. Proc Natl Acad Sci USA 76:3552–3556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trapp BD, Dubois-Dalcq M, Quarles RH (1984) Ultrastructural localization of P2 protein in actively myelinating rat Schwann cells. J Neurochem 43:944–948

    Article  CAS  PubMed  Google Scholar 

  • Uyemura K, Yoshimura K, Suzuki M, Kitamura K (1984) Lipid binding activities of the P2 protein in peripheral nerve myelin. Neurochem Res 9:1509–1514

    Article  CAS  PubMed  Google Scholar 

  • Wu LM, Williams A, Delaney A, Sherman DL, Brophy PJ (2012) Increasing internodal distance in myelinated nerves accelerates nerve conduction to a flat maximum. Curr Biol 22:1957–1961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zenker J et al (2014) A role of peripheral myelin protein 2 in lipid homeostasis of myelinating Schwann cells. Glia 62:1502–1512

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The excellent technical assistance of Zippora Kohne and Jean-Jacques Médard is greatly appreciated. We thank Kathleen Ingenhoven for her great support in the lab.

Funding

No funding was received for the current study.

Author information

Authors and Affiliations

  1. Department of Neurology, University Hospital Essen, Essen, Germany

    Mark Stettner, Fabian Szepanowski, Anne K. Mausberg & Christoph Kleinschnitz

  2. Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany

    Fabian Klingler, Hans-P. Hartung & Bernd C. Kieseier

  3. Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Singapore, Singapore

    Jennifer Zenker

  4. Department of Neuroscience and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Roman Chrast

Authors
  1. Mark Stettner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennifer Zenker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fabian Klingler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fabian Szepanowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hans-P. Hartung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anne K. Mausberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christoph Kleinschnitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Roman Chrast
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bernd C. Kieseier
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Authors’ Contributions

Study concept and design: MS, and BK. Acquisition of data: MS, FK, FS, JPW, TD, AKM. Analysis and interpretation of data: MS, JZ, RC, BCK. Drafting of the manuscript: MS, and BK. Critical revision of the manuscript for important intellectual content: MS, BK, JZ, RC, CK. Statistical analysis: MS, FK, FS, AKM. BK. Study supervision: MS, and BK. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Mark Stettner.

Ethics declarations

Competing interest

The authors declare that they have no competing interests.

Informed Consent

The manuscript does not contain any individual person’s data in any form. Not applicable.

Ethical Approval

All experiments implicating animals were performed in accordance with the legal requirements of the University of Düsseldorf and the “Landesamt für Natur- und Umweltschutz Nordrhein-Westfalen” (Regional Office for Nature, Environment and Consumer Protection), Germany.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stettner, M., Zenker, J., Klingler, F. et al. The Role of Peripheral Myelin Protein 2 in Remyelination. Cell Mol Neurobiol 38, 487–496 (2018). https://doi.org/10.1007/s10571-017-0494-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-017-0494-0

Keywords

Search

Navigation