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

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.

Molecular rotors report on changes in live cell plasma membrane microviscosity upon interaction with beta-amyloid aggregates

“…84 As we have previously shown, both S100A4 and H3 protect neurons from apoptosis and oxidative stress in vitro and in animal models of brain trauma, epilepsy and nerve degeneration. 84,85 These effects are mediated by several plasma membrane receptors triggering intracellular signalling cascades 84,86 ; however, the effect of S100A4 or its derivatives on biophysical properties of cell membranes has not yet been investigated. We therefore tested whether treatment with the neuroprotective H3 peptide affects membrane microviscosity of non-treated and/or Aβ-treated SH-SY5Y cells.…”

Role of metastasis-induced protein S100A4 in human non-tumor pathophysiologies

“…Its expression also increases in a sub-population of neurons (mainly sensory and autonomic) [ 74 ]. Similar to the central nervous system, S100A4 exerts pro-regenerative and pro-survival effects in an injured peripheral nervous system, and mimetic peptides derived from neurotrophic motifs of S100A4 contribute to axonal sprouting and survival [ 75 ].…”

Persistent alterations in active and passive electrical membrane properties of regenerated nerve fibers of man and mice

“…Sciatic nerves were crushed in 7–8‐week‐old mice under a stereomicroscope (MZ6; Leica Microsystems, Ballerup, Denmark). The current lesion procedure was previously described in detail (Moldovan et al ., ; Rosberg et al ., ). Briefly, through a minimal incision after shaving the right hindlimb, the right sciatic nerve was crushed at mid‐thigh level (~ 1 cm above the knee) by clamping the nerve with a smooth‐jawed micro‐forceps for 30 s. After the crushing procedure the injured nerve remained in continuity and the crushed part appeared as a flattened translucent band.…”