Chaperone-mediated autophagy: the Achilles heel of the retinal pigment epithelium during age-related macular degeneration

Chaperone-mediated autophagy (CMA) is a selective autophagy pathway that targets specific proteins containing a KFERQ-like motif for lysosomal degradation. It has been shown by us and others that CMA decreases during physiological aging in most tissues, and its impairment is associated with increased incidence of age-related pathologies, such as cardiovascular disease, neurodegenerative disorders or sarcopenia. However, its involvement in age-related macular degeneration (AMD), a prevalent progressive maculopathy that leads to bilateral central vision loss, had not been explored. In the early stages of AMD, the retinal pigment epithelium (RPE), a monolayer of cells that provides trophic support to photoreceptors, already presents major morphological and functional alterations but the cause of this cell type-specific vulnerability is unknown. In our latest work, we analyzed human donor RPE samples and found that CMA is selectively impaired in the RPE of AMD patients compared to healthy donors. These alterations lead to the accumulation of undegraded CMA substrates and untimely recycling of other proteins. Crucially, these findings are conserved in donor-derived iPSC-RPE models. We used this clinically relevant model to assess the consequences of dysfunctional CMA in AMD and found that it caused proteotoxicity, increased oxidative damage, and altered metabolism. Most importantly, using the new-generation CMA activator CA77.1, we restored proteostasis in AMD iPSC-RPE. Our findings shed light on the selective vulnerability of the RPE in AMD and provide evidence in support of CMA as a novel druggable target against AMD.