Research
Ambra1+/gt mice display abnormalities in the retinal pigment epithelium (RPE) associated with premature aging. RPE morphology assessed by phalloidin (red) staining in RPE flat mounts from middle-aged Ambra1+/+ and Ambra1+/gt littermates, showing increases in cell size and lesion site number in the RPE monolayer in Ambra1+/gt mice (left).
22 Aug 2022
The Autophagy regulator Ambra1 sustains metabolism and protects against aging and retinal degeneration
A work publish in the journal Autophagy by the group of Dr. Patricia Boya has demonstrated how autophagy protects the retina against stress and physiological aging, describing a retinal phenotype consistent with accelerated aging in mice that carry deficiencies in the pro-autophagic gene Ambra1.
Macroautophagy/autophagy is a key process in the maintenance of cellular homeostasis. The age-dependent decline in retinal autophagy has been associated with photoreceptor degeneration. Retinal dysfunction can also result from damage to the retinal pigment epithelium (RPE), as the RPE-retina constitutes an important metabolic ecosystem that must be finely tuned to preserve visual function. While studies of mice lacking essential autophagy genes have revealed a predisposition to retinal degeneration, the consequences of a moderate reduction in autophagy, similar to that which occurs during physiological aging, remain unclear.
Ramírez-Pardo et al. described in this paper a retinal phenotype associated with accelerated aging in mice carrying haploinsufficiency for Ambra1. These mice showed protein aggregation in the retina and RPE, metabolic underperformance, and premature vision loss. Moreover, Ambra1+/gt mice were more prone to retinal degeneration after RPE stress. These findings indicate that autophagy provides crucial support to RPE-retinal metabolism and protects the retina.
Taken together, these data demonstrate that Ambra1 deficiency alters the retina-RPE ecosystem leading to RPE cell death, metabolic underperformance, loss of visual function, and increased susceptibility to stress. Additionally, they show that Ambra1 expression is selectively upregulated in the macular region of the RPE in Age-Related Macular Degeneration (AMD) patients, but not in the non-macular area.
Overall, the study demonstrates that AMBRA1-mediated autophagy may be a key process for preventing age- and stress-dependent RPE dysfunction and retinal degeneration.
Reference: Ambra1 haploinsufficiency in CD1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration. I. Ramírez-Pardo, B. Villarejo-Zori, J. I. Jiménez-Loygorri, E. Sierra-Filardi, S. Alonso-Gil, G. Mariño, P. de la Villa, P. S. Fitze, J. M. Fuentes, R. García-Escudero, D. A. Ferrington, R. Gomez-Sintes and P. Boya (2022) Autophagy.