The metastasis-promoting S100A4 protein confers neuroprotection in brain injury

Protein Laboratory, Institute of Neuroscience and Pharmacology, Panum Institute, Blegdamsvej 3C, Building 24.2, Copenhagen 2200N, Denmark.
Nature Communications (Impact Factor: 11.47). 11/2012; 3:1197. DOI: 10.1038/ncomms2202
Source: PubMed


Identification of novel pro-survival factors in the brain is paramount for developing neuroprotective therapies. The multifunctional S100 family proteins have important roles in many human diseases and are also upregulated by brain injury. However, S100 functions in the nervous system remain unclear. Here we show that the S100A4 protein, mostly studied in cancer, is overexpressed in the damaged human and rodent brain and released from stressed astrocytes. Genetic deletion of S100A4 exacerbates neuronal loss after brain trauma or excitotoxicity, increasing oxidative cell damage and downregulating the neuroprotective protein metallothionein I+II. We identify two neurotrophic motifs in S100A4 and show that these motifs are neuroprotective in animal models of brain trauma. Finally, we find that S100A4 rescues neurons via the Janus kinase/STAT pathway and, partially, the interleukin-10 receptor. Our data introduce S100A4 as a therapeutic target in neurodegeneration, and raise the entire S100 family as a potentially important factor in central nervous system injury.

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Available from: Oksana Dmytriyeva, Jan 30, 2015
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    • "Intracellular S100A4 controls signal transduction through FcγRIIIA by inhibiting the activation of the tyrosine kinase Syk [23]. S100A4 is described as an essential partner of the JAK/ STAT signal transduction activating receptors to IL7 in chondrocytes [24] and IL10 in the cells of neuroglia [25]. S100A4 is required for the IL1 receptor dependent activation of an ERK–p38–JNK signalling pathway [26] and for mediating estrogen effects to bone progenitors [27]. "
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    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, termed 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. Based on 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 myelin protein P0 null mice, a model of dysmyelinating neuropathy (Charcot-Marie-Tooth 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 CMT. 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.
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