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Proteases

Unravelling the therapeutic activity of activated protein C

Nature Reviews Drug Discovery volume 9, pages 20–21 (2010)Cite this article

In The Journal of Clinical Investigation, Zlokovic and colleagues report that, in a mouse model of ALS, administration of APC or APC analogues after disease onset slowed disease progression and extended survival. They found that APC injected into mice expressing an ALS-linked mutant of human superoxide dismutase 1 (SOD1), SOD1G93A, crossed the blood–spinal cord barrier (BSCB) through the endothelial receptor for protein C and lowered SOD1 expression in motor neurons, microglia and endothelial cells in spinal cord microvessels.

Interestingly, the serine protease activity of APC, but not its anticoagulant activity, was crucial for the effects in slowing disease progression, suggesting the involvement of protease-activated receptors (PARs), which mediate the transmembrane signalling of APC. Using PAR-specific blocking antibodies, the authors showed that PAR1 and PAR3 are required for the APC-mediated downregulation of SOD1.

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ORIGINAL RESEARCH PAPERS

  1. Zhong, Z. et al. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J. Clin. Invest. 119, 3437–3449 (2009)

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  2. Xu, J. et al. Extracellular histones are major mediators of death in sepsis. Nature Med. 15, 1318–1321 (2009)

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Authors
  1. Monica Hoyos Flight
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Flight, M. Unravelling the therapeutic activity of activated protein C. Nat Rev Drug Discov 9, 20–21 (2010). https://doi.org/10.1038/nrd3082

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