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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.

SUBMITTER: Bell K

PROVIDER: S-EPMC7165178 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Bell Katharina K Rosignol Ines I Sierra-Filardi Elena E Rodriguez-Muela Natalia N Schmelter Carsten C Cecconi Francesco F Grus Franz F Boya Patricia P

Cell death discovery 20200417

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 curre ...[more]

PMID: 32337073

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Project description:The pleotropic cytokine interleukin-6 (IL-6) is implicated in retinal ganglion cell (RGC) survival and degeneration, including that associated with glaucoma. IL-6 protects RGCs from pressure-induced apoptosis in vitro. However, it is unknown how IL-6 impacts glaucomatous degeneration in vivo. To study how IL-6 influences glaucomatous RGC axonopathy, accompanying glial reactivity, and resultant deficits in visual function, we performed neural tracing, histological, and neurobehavioral assessments in wildtype (B6;129SF2/J; WT) and IL-6 knock-out mice (B6;129S2-IL6tm1kopf/J; IL-6-/-) after 8 weeks of unilateral or bilateral microbead-induced glaucoma (microbead occlusion model). IOP increased by 20% following microbead injection in both genotypes (p < 0.05). However, deficits in wound healing at the site of corneal injection were noted. In WT mice, elevated IOP produced degenerating axon profiles and decreased axon density in the optic nerve by 15% (p < 0.01). In IL-6-/- mice, axon density in the optic nerve did not differ between microbead- and saline-injected mice (p > 0.05) and degenerating axon profiles were minimal. Preservation of RGC axons was reflected in visual function, where visual acuity decreased significantly in a time-dependent manner with microbead-induced IOP elevation in WT (p < 0.001), but not IL-6-/- mice (p > 0.05). Despite this preservation of RGC axons and visual acuity, both microbead-injected WT and IL-6-/- mice exhibited a 50% decrease in anterograde CTB transport to the superior colliculus, as compared to saline-injected controls (p < 0.01). Assessment of glial reactivity revealed no genotype- or IOP-dependent changes in retinal astrocytes. IOP elevation decreased microglia density and percent retinal area covered in WT mice (p < 0.05), while IL-6-/- mice exhibited only a decrease in density (p < 0.05). Together, our findings indicate that two defining features of RGC axonopathy-axon transport deficits and structural degeneration of axons-likely occur via independent mechanisms. Our data suggest that IL-6 is part of a mechanism that specifically leads to structural degeneration of axons. Furthermore, its absence is sufficient to prevent both structural degeneration of the optic nerve and vision loss. Overall, our work supports the proposition that functional deficits in axon transport represent a therapeutic window for RGC axonopathy and identify IL-6 signaling as a strong target for such a therapeutic.

Dataset Information

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

Publications

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

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