Poly(ADP-ribose) polymerase-1 activation in a primate model of multiple sclerosis.
Multiple sclerosis (MS) is an immune-mediated disabling neurological disorder involving inflammation, demyelination, axonal damage, and neurodegeneration. Poly(ADP-ribose)polymerase-1 (PARP-1), a nuclear enzyme linked to DNA repair, has been shown to regulate the cellular inflammatory response through interactions with nuclear factor-kappaB. Extensive PARP-1 activation can, by separate mechanisms, also cause cell death. PARP-1 activation in brain occurs in several settings associated with oxidative stress and DNA damage, and PARP-1 inhibition has been shown to attenuate inflammation and improve neuronal survival in these settings. Here we studied the pattern of PARP-1 activation in a nonhuman primate model of MS, marmoset (Callithrix jacchus) experimental allergic encephalomyelitis (EAE). Characteristic of this model is relapsing and remitting focal demyelination typical of human MS. Immunostaining for poly(ADP-ribose), the enzymatic product of PARP-1, showed PARP-1 activation specifically in plaque areas of EAE brains. Robust immunostaining was found in astrocytes surrounding demyelinated EAE plaques and in scattered nearby microglia, oligodendrocytes, and neurons. The immunostaining also suggested PARP-1 activation in occasional endothelial cells surrounded by microglia or infiltrating peripheral blood cells. Given the importance of PARP-1 in both inflammation and cell death processes, these findings suggest that PARP-1 activation may be a significant factor in the pathogenesis of MS.
Kauppinen
Tiina M
TM
Department of Neurology, University of California at San Francisco, San Francisco, CA 94121, USA.
Suh
Sang Won
SW
Genain
Claude P
CP
Swanson
Raymond A
RA
D000818:Animals; D002144:Callithrix; D003711:Demyelinating Diseases / Q000201:enzymology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D017628:Microglia / Q000201:enzymology* / Q000473:pathology; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
D011065:Poly(ADP-ribose) Polymerases