Chaperone-mediated autophagy protects against retinal photoreceptor degeneration by modulating proteostasis of glucose metabolism enzymes
Abstract
Defective proteostasis is a hallmark of aging cells and tissues. Among the different components of the proteostasis network, in this study, we focus on a selective form of autophagy known as chaperone-mediated autophagy (CMA), and we set out to understand its physiological role in the retina. Using mice deficient for CMA [knockout for lysosome-associated membrane protein type 2A ( Lamp2A )], we have found that CMA blockade leads to impaired visual function, altered retinal proteostasis, and photoreceptor cell death. Conversely, mice that overexpress human LAMP2A show higher resistance to chemically induced photoreceptor degeneration and slower visual function decline. We found a similar protective effect against retinal degeneration upon pharmacological activation of CMA. To start elucidating the mechanisms behind CMA’s protective role in the retina, we used comparative proteomics and found elevated levels of enzymes related with glucose metabolism in CMA-deficient retinas that phenocopy those observed in old mice retinas. Overall, our results highlight a cytoprotective role for CMA in retina, in part through proteostatic regulation of enzymes involved in glucose metabolism, and support the feasibility of pharmacologically upregulating CMA against retinal degeneration.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (13)
Raquel Gómez-Sintes
Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas Margarita Salas, Consejo superior de Investigaciones Científicas (CSIC)
Inmaculada Tasset
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine
Ignacio Ramírez-Pardo
Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas Margarita Salas, Consejo superior de Investigaciones Científicas (CSIC)
Adrián Martín-Segura
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine
Sandra Alonso-Gil
Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas Margarita Salas, Consejo superior de Investigaciones Científicas (CSIC)
Antonio Díaz
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine
Kristen Lindenau
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine
Concepción Lillo
Departamento Biología Celular y Patología, Instituto de Neurociencias de Castilla y León (INCYL), Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca
Pedro de la Villa
University of Alcalá de Henares (UAH), Pl. de San Diego, s/n, Alcalá de Henares, Madrid 28801, Spain
Simone Sidoli
Evripidis Gavathiotis
Ana María Cuervo
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine
Patricia Boya
Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas Margarita Salas, Consejo superior de Investigaciones Científicas (CSIC)