Abstract
Purpose :
Oxidative stress has been implicated in the pathophysiology of glaucoma; however, the biological mechanisms by which oxidative damage causes retinal ganglion cell (RGC) death remain to be elucidated. We previously reported that oxidative DNA damage triggers microglial activation and retinal degeneration via the activation of MutY Homolog (MUTYH), a DNA damage-associated glycosylase, in experimental retinitis pigmentosa. In the present study, we investigate the role of MUTYH in RGC cell death induced by N-methyl-D-aspartate (NMDA).
Methods :
Mutyh-/- mice and age-matched wild-type (WT) mice was employed in a model of NMDA-induced retinal excitotoxicity. Eight nM NMDA was intravitreally injected in the mouse eyes. Immunohistochemical analysis was performed using anti-8-hydoroxy-deoxyguanosine (8-oxoG) monoclonal antibody (a marker of oxidative DNA damage), anti-Brn3a antibody (a marker of RGC), anti-Iba-1 antibody (a marker of microglia), and anti-ssDNA antibody [a marker of single strand breaks (SSBs)] at 24 hours and 7 days after injection.
Results :
Substantial microgliosis and RGC loss were observed in the eyes of NMDA-injected WT mice. In contrast, Mutyh deficiency significantly reduced the density of microglia (P = 0.0152) and attenuated the RGC loss (P = 0.0021). Moreover, 8-oxoG was accumulated within the nucleus of microglia after 24 hours to 7 days and SSBs were developed in WT mice. In contrast, Mutyhdeficiency prevented SSBs formation following NMDA-induced oxidative DNA damage.
Conclusions :
MUTYH activation associated with oxidative DNA damage accelerates microgliosis and RGC cell death in NMDA-induced retinal excitotoxicity.
This is a 2021 ARVO Annual Meeting abstract.