Ambra1 haploinsufficiency results in metabolic alterations and exacerbates age-associated retinal degeneration

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 importa...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Ramirez-Pardo, Ignacio, Villarejo-Zori, Beatriz, Jimenez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Alonso-Gil, Sandra, Mariño, Gillermo, De La Villa, Pedro, Fitze, Patrick S, Fuentes, Jose Manuel, Garcia-Escudero, Ramon, Gomez-Sintes, Raquel, Boya, Patricia
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 05.02.2022
Subjects
Aging
Autophagy
Epithelium
Haploinsufficiency
Homeostasis
Metabolism
Phenotypes
Physiology
Protein interaction
Retina
Retinal degeneration
Retinal pigment epithelium
Visual perception
Online AccessGet full text

Cover

More Information
Summary: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 which occurs with physiological aging, remain unclear. Here, we describe a retinal phenotype consistent with accelerated aging in mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene. These mice show protein aggregation in the retina and the RPE, display metabolic underperformance and premature vision loss. Moreover, Ambra1+/gt mice are more prone to retinal degeneration after RPE stress. These findings point to autophagy as a key process to support the RPE-retinal metabolism and protect the retina against stress and physiological aging. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2022.02.04.476630