The metastasis-promoting S100A4 protein confers neuroprotection in brain injury

Oksana Dmytriyeva, Stanislava Pankratova, Sylwia Owczarek, Katrin Sonn, Vladislav Soroka, Christina M. Ridley, Alexander Marsolais, Marcos Lopez-Hoyos, Noona Ambartsumian, Eugene Lukanidin, Elisabeth Bock, Vladimir Berezin and Darya Kiryushko ()
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Oksana Dmytriyeva: Protein Laboratory, Institute of Neuroscience and Pharmacology, Panum Institute
Stanislava Pankratova: Protein Laboratory, Institute of Neuroscience and Pharmacology, Panum Institute
Sylwia Owczarek: Protein Laboratory, Institute of Neuroscience and Pharmacology, Panum Institute
Katrin Sonn: University of Tartu
Vladislav Soroka: Protein Laboratory, Institute of Neuroscience and Pharmacology, Panum Institute
Christina M. Ridley: Protein Laboratory, Institute of Neuroscience and Pharmacology, Panum Institute
Alexander Marsolais: Protein Laboratory, Institute of Neuroscience and Pharmacology, Panum Institute
Marcos Lopez-Hoyos: Service of Immunology, Hospital Universitario Marqués de Valdecilla - IFIMAV
Noona Ambartsumian: Institute of Cancer Biology, Danish Cancer Society
Eugene Lukanidin: Institute of Cancer Biology, Danish Cancer Society
Elisabeth Bock: Protein Laboratory, Institute of Neuroscience and Pharmacology, Panum Institute
Vladimir Berezin: Protein Laboratory, Institute of Neuroscience and Pharmacology, Panum Institute
Darya Kiryushko: Protein Laboratory, Institute of Neuroscience and Pharmacology, Panum Institute

Nature Communications, 2012, vol. 3, issue 1, 1-11

Abstract: 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+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.

Date: 2012
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DOI: 10.1038/ncomms2202

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