Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 24, Pages 9461-9475Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.008697
Keywords
retina; vitamin A; vision; retinal degeneration; rhodopsin; all-trans-retinal (atRAL); high-throughput screen (HTS); estrogen receptor (ER); selective estrogen receptor modulator (SERM); photoreceptor degeneration; blindness; cytotoxicity; cell death
Categories
Funding
- NEI, National Institutes of Health [R24EY024864, R24EY027283, EY024992, T32GM007250, F30EY029136-01A1, R01EY027691]
- Research to Prevent Blindness
- Canadian Institute for Advanced Research (CIFAR)
- Alcon Research Institute (ARI)
Ask authors/readers for more resources
The retinoid cycle is a metabolic process in the vertebrate retina that continuously regenerates 11-cis-retinal (11-cisRAL) from the all-trans-retinal (atRAL) isomer. atRAL accumulation can cause photoreceptor degeneration and irreversible visual dysfunction associated with incurable blinding retinal diseases, such as Stargardt disease, retinitis pigmentosa (RP), and atrophic age-related macular degeneration (AMD). The underlying cellular mechanisms leading to retinal degeneration remain uncertain, although previous studies have shown that atRAL promotes calcium influx associated with cell apoptosis. To identify compounds that mitigate the effects of atRAL toxicity, here we developed an unbiased and robust image-based assay that can detect changes in intracellular calcium levels in U2OS cells. Using our assay in a high-throughput screen of 2,400 compounds, we noted that selective estrogen receptor modulators (SERMs) potently stabilize intracellular calcium and thereby counteract atRAL-induced toxicity. In a light-induced retinal degeneration mouse model (Abca4(-/-)Rdh8(-/-)), raloxifene (a benzothiophene-type scaffold SERM) prevented the onset of photoreceptor apoptosis and thus protected the retina from degeneration. The minor structural differences between raloxifene and one of its derivatives (Y 134) had a major impact on calcium homeostasis after atRAL exposure in vitro, and we verified this differential impact in vivo. In summary, the SERM raloxifene has structural and functional neuroprotective effects in the retina. We propose that the highly sensitive image-based assay developed here could be applied for the discovery of additional drug candidates preventing photoreceptor degeneration.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available