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Kai Kaarniranta; Circadian control and proteostasis in NRF-2/PGC-1 alpha knock-out mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1588.
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Presentation Description :
Circadian clocks in the eye are critical for normal visual function, but their disruption can lead to degenerative diseases, such as age-related macular degeneration (AMD). It has been suggested that AMD pathogenesis involves increased oxidative stress and impaired protein degradation in retinal pigment epithelial cells (RPE). The ubiquitin-proteasome pathway and the lysosomal/autophagosomal pathway are the major proteolytic systems in eukaryotic cells. The RPE cells are constantly exposed to oxidative stress that may lead to damage and accumulation of cellular proteins, DNA and lipids and evoke tissue damage during aging process. The nuclear factor-erythroid 2-related factor-2 (NRF-2) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) are master transcription factors in the regulation of cellular detoxification. We investigated the role of NRF-2 and PGC-1 α in the regulation of RPE cell structure and function by using global single and double knockout (dKO) mice. The NRF-2/PGC-1α dKO mice exhibited age-dependent RPE degeneration, accumulation of oxidative stress marker 4-HNE[J1] and ER stress markers GRP78 and ATF4. Moreover, ubiquitinated protein conjugates and autophagy markers SQSTM1/p62, Beclin-1 and MAP1LC3A/LC3 were upregulated together with increased Iba-1 macrophage marker staining and the enlargement of RPE size. These histopathological changes were accompanied by visual loss as revealed by electroretinography. Electroretinograms changed according to circadian rhythm and gene defects. Consequently, these novel discoveries suggest that the NRF-2 and PGC-1α knock-out mice are valuable for investigating the role of circadian rhythm and proteostasis in the RPE and in the development of AMD. [J1]Should be explained, likewise further abbreviations
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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