The metastasis-promoting S100A4 protein confers neuroprotection in brain injury

Abstract

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 þ 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.

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

“…These findings suggest that S100A4 may, in addition to its conventional role in carcinogenesis, also modulate posttraumatic events in the nervous system. Supporting this hypothesis, we recently found that S100A4 knockout increases neuronal loss after traumatic brain injury and identified two neurotrophic motifs in the S100A4 sequence (10). Synthetic peptides corresponding to these motifs (H3 and H6)…”

“…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 also affect PNS regeneration after injury.…”

“…Thereafter, the sections were processed and stained by using the above-described protocol for S100 immunostaining and rabbit anti-mouse S100A4 antibodies (1:2,000; characterized by Dmytriyeva et al [10]). …”

“…In the lesioned brain, S100A4 is upregulated in the white matter astrocytes outlining the trauma site (9) and is also detected in the hippocampus after excitotoxic injury (10). S100A4 is also overexpressed by the astrocytes of the spinal cord adjacent to the site of spinal transection (11).…”

“…S100A4 is also overexpressed by the astrocytes of the spinal cord adjacent to the site of spinal transection (11). 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, also modulate posttraumatic events in the nervous system.…”