Defective chaperone-mediated autophagy in the retinal pigment epithelium of age-related macular degeneration patients
Juan Ignacio Jiménez‐Loygorri, Peng Shang, Ibrahim Bayramoglu, Raquel Gómez‐Sintes, Adrián Martín‐Segura, Helena Ambrosino, Johnson Hoang, Antonio Díaz, Zhaohui Geng, Evripidis Gavathiotis, James R. Dutton, Jörn Dengjel, Ana María Cuervo, Deborah A. Ferrington, Patricia Boya
Abstract
Autophagy is one of the main intracellular recycling systems and its impairment is considered a primary hallmark of the aging process. Defective macroautophagy in the retinal pigment epithelium (RPE) has been described in age-related macular degeneration (AMD), a blindness-causing disease that affects roughly 200 million patients worldwide. The relevance of chaperone-mediated autophagy (CMA), a selective type of autophagy for proteins containing a KFERQ-like motif, in RPE cell biology and homeostasis remains to be elucidated. Here we describe decreased CMA activity in the RPE of AMD patients compared to healthy age-matched controls, along with accumulation of substrate proteins, and in donor-derived iPSC-RPE cells, which we used to further characterize AMD-associated alterations of cellular homeostasis derived from proteotoxicity. Treatment with CA77.1 (CMA activator) restores proteostasis and remodels specific subsets of the proteome in cells from healthy and AMD donors. CA77.1-treated AMD iPSC-RPE display reduced oxidative stress and improved mitochondrial function. These findings may explain the specific vulnerability of the RPE during AMD and shed light on CMA as a new druggable target for this as-of-now incurable disease.