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Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets

Author

Listed:
  • May H. Han

    (Department of Neurology and Neurological Sciences,)

  • Sun-Il Hwang

    (Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA)

  • Dolly B. Roy

    (Northridge Neurological Center, Northridge, California 91325, USA)

  • Deborah H. Lundgren

    (Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA)

  • Jordan V. Price

    (Department of Neurology and Neurological Sciences,)

  • Shalina S. Ousman

    (Department of Neurology and Neurological Sciences,)

  • Guy Haskin Fernald

    (University of California at San Francisco School of Medicine)

  • Bruce Gerlitz

    (Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA)

  • William H. Robinson

    (Stanford University School of Medicine, Stanford, California 94305, USA)

  • Sergio E. Baranzini

    (University of California at San Francisco School of Medicine)

  • Brian W. Grinnell

    (Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA)

  • Cedric S. Raine

    (Albert Einstein College of Medicine, Bronx, New York 10461, USA)

  • Raymond A. Sobel

    (Stanford, California 94305, USA)

  • David K. Han

    (Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA)

  • Lawrence Steinman

    (Department of Neurology and Neurological Sciences,)

Abstract

Understanding the neuropathology of multiple sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits. Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque. Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation. In vivo administration of hirudin or recombinant activated protein C reduced disease severity in experimental autoimmune encephalomyelitis and suppressed Th1 and Th17 cytokines in astrocytes and immune cells. Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of experimental autoimmune encephalomyelitis. A proteomic approach illuminated potential therapeutic targets selective for specific pathological stages of MS and implicated participation of the coagulation cascade.

Suggested Citation

  • May H. Han & Sun-Il Hwang & Dolly B. Roy & Deborah H. Lundgren & Jordan V. Price & Shalina S. Ousman & Guy Haskin Fernald & Bruce Gerlitz & William H. Robinson & Sergio E. Baranzini & Brian W. Grinnel, 2008. "Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets," Nature, Nature, vol. 451(7182), pages 1076-1081, February.
    • Handle: RePEc:nat:nature:v:451:y:2008:i:7182:d:10.1038_nature06559
    DOI: 10.1038/nature06559
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