Abstract
Purpose :
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) encoded by the PPARGC1A gene regulates cellular antioxidant defense and oxidative stress along with cellular senescence and impaired autophagy are major factors of age-related macular degeneration (AMD) pathogenesis. We tested the hypothesis that PGC-1a was important for the interplay between oxidative stress, autophagy and senescence in the retinal pigment epithelium (RPE) using an experimental model comprising mice with knockout in PPARGC1A (PPARGC1A-KO mice) and wild-type (WT) animals.
Methods :
PPARGC1A-KO mice were derived from the C57BL/6J strain. Sections of the RPE/choroid from mouse eyes were mounting and observed in a confocal microscope. Gene expression was evaluated by immunochemistry. ANOVA and Dunnet multiple comparison test were used in results analysis. All animal experiments were performed in agreement with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and approved by the Project Authorization Board of Regional Administrative Agency for Southern Finland (ESAVI/8621/04.10.07/2017).
Results :
We observed an increase in the expression of the following markers of autophagy: ubiquitin, SQSTM1 (Sequestosome 1), BCN1 (Beclin 1), LC3 (all p < 0.001), and LAMP2 (Lysosomal Associated Membrane Protein 2) (p < 0.05) in PPARGC1A-KO mice as compared with wild-type (WT) animals. In addition, the PINK1 (PTEN Induced Kinase 1)/PARKIN (Parkin RBR E3 Ubiquitin Protein Ligase) ratio increased in KO animals (p < 0.01). An increase in the cellular senescence markers BHLHE40 (Basic Helix-Loop-Helix Family Member E40) and HMGB1 (High Mobility Group Box 1) (both p < 0.001) was observed in KO mice as compared with WT animals.
Conclusions :
PGC-1α is involved in the regulation of senescence, autophagy and oxidative stress in the RPE. Therefore, PGC-1α plays an important role in AMD etiology and mice with knockout of the PPARGC1A gene may serve to study molecular aspects of AMD pathogenesis.
Acknowledgement. This work was supported by National Science Centre, Poland grant number 2017/27/B/NZ3/00872.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.