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Molecular Medicine

, Volume 19, Issue 1, pp 43–53 | Cite as

Peptide Mimetic of the S100A4 Protein Modulates Peripheral Nerve Regeneration and Attenuates the Progression of Neuropathy in Myelin Protein P0 Null Mice

  • Mihai Moldovan
  • Volodymyr Pinchenko
  • Oksana Dmytriyeva
  • Stanislava Pankratova
  • Kåre Fugleholm
  • Jorg Klingelhofer
  • Elisabeth Bock
  • Vladimir Berezin
  • Christian Krarup
  • Darya Kiryushko
Research Article

Abstract

We recently found that S100A4, a member of the multifunctional S100 protein family, protects neurons in the injured brain and identified two sequence motifs in S100A4 mediating its neurotrophic effect. Synthetic peptides encompassing these motifs stimulated neuritogenesis and survival in vitro and mimicked the S100A4-induced neuroprotection in brain trauma. Here, we investigated a possible function of S100A4 and its mimetics in the pathologies of the peripheral nervous system (PNS). We found that S100A4 was expressed in the injured PNS and that its peptide mimetic (H3) affected the regeneration and survival of myelinated axons. H3 accelerated electrophysiological, behavioral and morphological recovery after sciatic nerve crush while transiently delaying regeneration after sciatic nerve transection and repair. On the basis of the finding that both S100A4 and H3 increased neurite branching in vitro, these effects were attributed to the modulatory effect of H3 on initial axonal sprouting. In contrast to the modest effect of H3 on the time course of regeneration, H3 had a long-term neuroprotective effect in the myelin protein P0 nul mice, a model of dysmyelinating neuropathy (Charcot-Marie-Tooth type 1 disease), where the peptide attenuated the deterioration of nerve conduction, demyelination and axonal loss. From these results, S100A4 mimetics emerge as a possible means to enhance axonal sprouting and survival, especially in the context of demyelinating neuropathies with secondary axonal loss, such as Charcot-Marie-Tooth type 1 disease. Moreover, our data suggest that S100A4 is a neuroprotectant in PNS and that other S10C proteins, sharing high homology in the H3 motif, may have important functions in PNS pathologies.

Notes

Acknowledgments

The project was supported by the Lundbeck Foundation, Novo Nordisk Foundation, Danish Medical Research Council, Ludvig and Sara Elsass Foundation, Foundation for Research in Neurology and the Jytte and Kaj Dahlboms Foundation. We would like to thank Irina Korshunova for help with genotyping the P0 mice and Lis Hansen for expert technical assistance with the histological preparations.

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Authors and Affiliations

  • Mihai Moldovan
    • 1
  • Volodymyr Pinchenko
    • 1
    • 2
  • Oksana Dmytriyeva
    • 2
  • Stanislava Pankratova
    • 2
  • Kåre Fugleholm
    • 3
  • Jorg Klingelhofer
    • 2
  • Elisabeth Bock
    • 2
  • Vladimir Berezin
    • 2
  • Christian Krarup
    • 1
    • 4
  • Darya Kiryushko
    • 2
  1. 1.Nerve Laboratory, Department of Neuroscience and Pharmacology, Panum InstituteUniversity of CopenhagenCopenhagenDenmark
  2. 2.Protein Laboratory, Department of Neuroscience and PharmacologyUniversity of CopenhagenCopenhagenDenmark
  3. 3.Department of NeurosurgeryRigshospitalet, CopenhagenCopenhagenDenmark
  4. 4.Department of Clinical NeurophysiologyRigshospitaletCopenhagenDenmark

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