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Katharina Bell, Ines Rosignol, elena Sierra-Filardi, Carsten Schmelter, Franz H Grus, Patricia Boya; Age related RGC vulnerability in an autophagy deficient mouse model. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2360.
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© ARVO (1962-2015); The Authors (2016-present)
Glaucoma is an age-related neurodegenerative disease and one of the world’s leading causes for blindness. In this study we analyse the age related RGC susceptibility in context of autophagy impairment using Ambra1+/gt mice. Ambra1 is involved in autophagy induction, but also mitophagy. We also aimed to understand differences between WT and HT animals after ONC in greater detail.
Optic nerve crush was performed in 4 and 13-month-old Ambra1+/gt HT mice and Ambra1+/+ WT controls. RGCS were stained with Gamma-synuclein and Brn3a in flatmounts and cryosections. RGC counts were performed 7days after ONC. qPCR analysis of oxidative stress response markers and mitophagy receptors in the retina was performed 3 and 7 days post-ONC and control eyes. Proteomic analysis of HT and WT retinae was performed using an ESI-Orbitrap-MS system.
Young Ambra1+/gt (HT) or Ambra1+/+ (WT) showed the same amount of RGC cell survival 7 days after ONC (47% vs. 45%). However significant differences in cell survival could be detected when comparing aged Ambra1 HT with Ambra1 WT animals (71% decrease in RGCS in comparison to 53%; p<0.01). No significant RGC survival after ONC was found comparing young and old WT animals. Oxidative stress response was significantly altered in old HT animals after ONC (reduced levels of Nrf2, NQO1 and GPX1, p<0.05) as well as in control conditions (1.41 fold NQO1 increase in HT, p<0.05). Mitophagy receptors failed to show an increase in mitophagy after ONC in HT animals (BNIP3l and BNIP3), in comparison to WT mice (1.31 and 1.4 fold change in WT; p<0.05) and also were altered in control conditions (1.3 fold BNIP3l increase in HT; p<0.05). Proteomic analysis point towards altered mitochondrial and oxidative stress pathways in HT retinae.
Higher RGC vulnerability in aged autophagy impaired Ambra1 HT animals could be result of altered oxidative stress response and failure in mitophagy induction after ONC. Additionally we believe that stress response mechanisms are already upregulated in HT animals in control conditions leading to decreased possible additional stress response.
This is a 2020 ARVO Annual Meeting abstract.
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