Retinal pigment epithelial cells (RPEs), a pigmented cell layer in the outer retina, are constantly exposed to photo-oxidative stress. Autophagy relieves the stress by removing oxidative protein adducts, protein aggregates, and damaged mitochondria. We previously found that miR-29 is downregulated in choroid/RPE tissue in a model of exudative age-related macular degeneration (AMD), suggesting that miR-29 deficiency may contribute to autophagy inhibition and AMD progression. Here we wanted to test whether overexpression of miR-29 in RPEs could enhance autophagy, thereby facilitating removal of drusen components. Indeed, overexpression of miR-29 in the RPEs increased autophagy, assessed by decreased protein levels of p62, increased lipid form of microtubule-associated protein light chain (LC3-II), and elevated autophagy flux. Furthermore, overexpression of miR-29 mitigated the formation of mutant αB-crystallin (R120G) protein aggregates. In probing the mechanism, we demonstrated that miR-29 post-transcriptionally repressed LAMPTOR1/p18 via targeting its 3'-UTRs of messenger RNA. MiR-29 overexpression and knockdown of LAMPTOR1/p18 led to limited mTORC1 recruitment to lysosomes and inhibition of mTORC1 activity. Altogether, miR-29 enhances autophagy which aids in removal of protein aggregates. These findings reveal a novel role of miR-29, which has the potential of being a therapeutic strategy for rescuing RPE degeneration in ocular disorders.
Keywords: Age-related macular degeneration; Autophagy; Drusen; LAMPTOR1/p18; Neurodegenerative disorders; Protein aggregation; TFEB; mTOR; p85α.
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