Age related retinal Ganglion cell susceptibility in context of autophagy deficiency.

Glaucoma is a common age-related disease leading to progressive retinal ganglion cell (RGC) death, visual field defects and vision loss and is the second leading cause of blindness in the elderly worldwide. Mitochondrial dysfunction and impaired autophagy have been linked to glaucoma and induction of autophagy shows neuroprotective effects in glaucoma animal models. We have shown that autophagy decreases with aging in the retina and that autophagy can be neuroprotective for RGCs, but it is currently unknown how aging and autophagy deficiency impact RGCs susceptibility and survival. Using the optic nerve crush model in young and olWelcome@1234d (autophagy/beclin-1 regulator 1) mice we analysed the contribution of autophagy deficiency on retinal ganglion cell survival in an age dependent context. Interestingly, old mice showed decreased RGC survival after optic nerve crush in comparison to old , an effect that was not observed in the young animals. Proteomics and mRNA expression data point towards altered oxidative stress response and mitochondrial alterations in old animals. This effect is intensified after RGC axonal damage, resulting in reduced oxidative stress response showing decreased levels of , as well as failure of induction in the old . Old also failed to show increase in and expression after optic nerve crush, a response that is found in the controls. Primary RGCs derived from mice show decreased neurite projection and increased levels of apoptosis in comparison to animals. Our results lead to the conclusion that oxidative stress response pathways are altered in old mice leading to impaired damage responses upon additional external stress factors.