The metastasis-promoting S100A4 protein confers neuroprotection in brain injury

Nat Commun. 2012;3:1197. doi: 10.1038/ncomms2202.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Brain Injuries / drug therapy
  • Brain Injuries / metabolism
  • Brain Injuries / pathology
  • Cell Death / drug effects
  • Cytoprotection* / drug effects
  • Female
  • Gene Deletion
  • HEK293 Cells
  • Humans
  • Janus Kinases / metabolism
  • Kainic Acid
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis / pathology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology*
  • Neuroprotective Agents / metabolism
  • Neurotoxins / toxicity
  • Oxidative Stress / drug effects
  • Peptides / pharmacology
  • Peptides / therapeutic use
  • Rats
  • Receptors, Interleukin-10 / metabolism
  • S100 Calcium-Binding Protein A4
  • S100 Proteins / chemistry
  • S100 Proteins / metabolism*
  • STAT Transcription Factors / metabolism
  • Seizures / drug therapy
  • Seizures / pathology
  • Up-Regulation / drug effects


  • Neuroprotective Agents
  • Neurotoxins
  • Peptides
  • Receptors, Interleukin-10
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • S100a4 protein, mouse
  • STAT Transcription Factors
  • S100A4 protein, human
  • Janus Kinases
  • Kainic Acid