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 null 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 S100 proteins, sharing high homology in the H3 motif, may have important functions in PNS pathologies.
Highlights
The multifunctional S100 protein family plays an important role in many human diseases and governs processes such as apoptosis, inflammation and cell motility [1,2,3]
We previously found that the S100A4 protein increases neuritogenesis and survival of primary neurons, and this effect is mediated by two motifs in the S100A4 sequence, H3 and H6 (Figure 1A) [10]
Because synthetic peptides corresponding to these motifs mimicked biological activities of S100A4 in animal models of brain trauma, we asked whether H3 and H6 affect peripheral nervous system (PNS) regeneration after injury
Summary
The multifunctional S100 protein family plays an important role in many human diseases and governs processes such as apoptosis, inflammation and cell motility [1,2,3]. In vitro studies have shown that S100A4 can be secreted by several cell types including astrocytes [10,12,13] and exert extracellular effects, such as promoting neurite outgrowth and survival of primary hippocampal and cerebellar neurons [10,14,15,16]. These findings suggest that S100A4 may, in addition to its conventional role in carcinogenesis, modulate posttraumatic events in the nervous system.
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