Age related retinal Ganglion cell susceptibility in context of autophagy deficiency

Abstract

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 Ambra1 +/gt (autophagy/beclin-1 regulator 1 +/gt) mice we analysed the contribution of autophagy deficiency on retinal ganglion cell survival in an age dependent context. Interestingly, old Ambra1 +/gt mice showed decreased RGC survival after optic nerve crush in comparison to old Ambra1 +/+ , 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 Ambra1 +/gt animals. This effect is intensified after RGC axonal damage, resulting in reduced oxidative stress response showing decreased levels of Nqo1, as well as failure of Nrf2 induction in the old Ambra1 +/gt. Old Ambra1 +/gt also failed to show increase in Bnip3l and Bnip3 expression after optic nerve crush, a response that is found in the Ambra1 +/+ controls. Primary RGCs derived from Ambra1 +/gt mice show decreased neurite projection and increased levels of apoptosis in comparison to Ambra1 +/+ animals. Our results lead to the conclusion that oxidative stress response pathways are altered in old Ambra1 +/gt mice leading to impaired damage responses upon additional external stress factors.

Autophagy in major human diseases

“…Whereas models of partial autophagy deficiency (i.e., atg4b − / − mice) do not display visual impairment under baseline conditions, they are characterized by accrued sensitivity to axonal damage (Rodriguez‐Muela et al , 2012 ). Likewise, Becn1 + / − animals exhibit exacerbated retinal damage upon prolonged exposure to bright light (Chen et al , 2013 ), and old ambra1 + / gt exhibit accrued sensitivity to optic nerve crush (Bell et al , 2020 ). Conditional rb1cc1 deletion in retinal pigment epithelium (RPE) leads to severe visual impairment, linked to reduced RPE proteostatic functions (Yao et al , 2015 ).…”

The interplay of autophagy and oxidative stress in the pathogenesis and therapy of retinal degenerative diseases

“…Many studies have reported that the mTOR inhibitor rapamycin is used to induce autophagy and treat glaucoma in rodent models [ 149 ], showing the promotion of RGC survival in the ischemia/reperfusion injury model caused by IOP elevation [ 150 ]. Autophagy decreases with aging in the retina, and the induction of autophagy shows neuroprotective effects in a glaucoma animal model [ 151 ]. Although most evidence shows that autophagy is protective in glaucoma, an opposing result showed that the inhibition of autophagy by 3-methyladenine (MA) alleviates acute axonal degeneration in a rat model [ 139 ].…”

The Role of Autophagy in Eye Diseases

“…In a similar model of optic nerve axotomy developed in aged autophagy-deficient transgenic mice, it was shown that old individuals were more susceptible to damage compared with young individuals. These aged mice showed alterations in the oxidative stress response and mitochondrial alterations that contributed to increased axonal damage in RGCs [67]. In another study, in a rat model of glaucoma, autophagy was shown to first occur in the dendrites of RGCs rather than in the cell cytoplasm.…”