Proteomic analysis of active multiple sclerosis lesions reveals therapeutic
targets
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.