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Age-related macular degeneration pathogenesis involves impaired protein degradation in retinal pigment epithelial (RPE) cells. The ubiquitin-proteasome system and the autophagy pathway are major proteolytic processes in eukaryotic cells. SQSTM1/p62 has been shown as a key player linking the proteasomal and lysosomal clearance systems. The present study investigated the effects of AICAR (AICA ribonucleotide, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) with/without MG-132 (proteasome inhibitor) on autophagy regulation in RPE cells.ARPE-19 cells were treated with MG-132 (5μM) and/or AICAR (2mM). p62 and MAP1LC3A/LC3 (LC3II) were analyzed by Western blotting. LC3 lipidation was used to study autophagic flux. Transmission electron microscopy was used to detect protein aggregates and autophagosomes. pDendra2-hLC3 construct was used to detect macroautophagy in confocal microscopy analysis.AICAR+MG-132 co-treatment induces autophagy clearance of p62 and increased LC3 lipidation. AICAR is able to completely abolish the MG-132-induced protein aggregation after 24 h treatment; at the same time, the co-treatment increases the number of autophagic vesicles. Cells treated with MG-132+AICAR exhibit a strong reduction of the perinuclear aggregates containing both LC3II and p62 proteins.Autophagy is emerging as a novel target of therapies aimed to counteract protein aggregation and improve cell viability. In this way, our findings indicate that AICAR could be useful in the acceleration of protein clearance in RPE cells.