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Casey Keuthan, John Ash; A unique role for PGC-1β in regulating photoreceptor resistance to oxidative stress. Invest. Ophthalmol. Vis. Sci. 2016;57(12):179.
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© ARVO (1962-2015); The Authors (2016-present)
Oxidative stress-induced mitochondrial dysfunction has been implicated as a major causative factor in both age-related and inherited retinal degenerations. Therapies directed at repairing damaged mitochondria have the potential to slow and prevent cell death. Peroxisome proliferator-activated receptor gamma coactivator 1 beta (PGC-1β) is a known regulator of mitochondrial biogenesis in a variety of high-energy tissues. This work aims to characterize the PGC-1β retinal knockout mouse under light stress and investigate its role in neuroprotection of photoreceptors.
Chx10 Cre; PGC-1βf/f mice were generated for a conditional knockout of PGC-1β in all retinal neurons and Müller glial cells. Dark-reared mice were exposed to mild bright light (cyclic 400 lux light) for 6 days. This is a model of chronic oxidative stress. Both retinal structure and function were monitored before and after exposure to chronic stress. Spectral domain Optical Coherence Tomography (SD-OCT) was used to study retinal morphology, and retinal function was measured by electroretinography (ERG). All procedures with animals were conducted in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.
Exposure to mild bright light did not kill photoreceptors in Cre negative control mice. However, in mice with the retina-specific knockout of PGC-1β, photoreceptors died under mild stress conditions. This was exhibited by outer nuclear layer thinning and reduced scotopic ERG amplitudes. All mice had normal retinal structure and function prior to light stress.
Our data showing that photoreceptors are extremely sensitive to mild light stress in the absence of retinal PGC-1β suggests that PGC-1β is essential for detoxifying or repair activities under conditions of chronic stress. Given the role of PGC-1 in regulating mitochondrial and oxidant defense genes, these findings support the use of PGC-1 family proteins as potential therapeutic targets to combat photoreceptor degeneration.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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