Ambra1 and its role during physiological ageing in the retina

from 2020 ARVO Annual Meeting, canceled because of COVID-19
Purpose : Ambra1 (activating-molecule in Beclin-1-regulated autophagy) is a protein that regulates the early stages of autophagy initiation. Ambra1 haploinsufficiency is linked to autophagy under several pathological conditions such as Alzheimer Disease, autism or multiple system atrophy. In the retina, there is a decline in the autophagy response upon ageing thus we aimed to test if Ambragt/+ haploinsufficiency might affect retinal ageing.
Methods : As Ambra1 homozigous animals are embryonic lethal, we have analised the phenotype of Ambra1gt/+ during aging and compared with Ambra1+/+ litermates. We have assessed retinal morphology and function with ERG in animals up to 24 months as well as compared the metabolic profile using mass spectrometry.
Results : Our results show that Ambra1gt/+ display premature death in comparison to control littermates. We also observe symptoms of premature retinal ageing in Ambra1gt/+ mice at 15 months old. This tendency was increased in geriatric animals (>20 months) as Ambra1gt/+ displayed increased inflammatory response and a reduction in the photoreceptor layer thickness. Finally, aged Ambra1gt/+ mice displayed a different metabolic signature indicating a misbalance in the purine metabolism and redox status.
Conclusions : This data suggest that autophagy deficiency results in a pro-ageing phenotype and impair retinal homeostasis and metabolism.