The Molecular Chaperone Sigma 1 Receptor Mediates Rescue of Retinal Cone Photoreceptor Cells Via Modulation of NRF2
Cell Biology and Anatomy
Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic target for retinal degenerative disease. Earlier studies showed that activation of Sig1R via the high-affinity ligand (+)-pentazocine ((+)-PTZ) induced profound rescue of cone photoreceptor cells in the rd10 mouse model of retinitis pigmentosa; however the mechanism of rescue is unknown. Improved cone function in (+)-PTZ-treated mice was accompanied by reduced oxidative stress and normalization of levels of NRF2, a transcription factor that activates antioxidant response elements (AREs) of hundreds of cytoprotective genes. Here, we tested the hypothesis that modulation of NRF2 is central to Sig1R-mediated cone rescue. Activation of Sig1R in 661W cone cells using (+)-PTZ induced dose-dependent increases in NRF2-ARE binding activity and NRF2 gene/protein expression, whereas silencing Sig1R significantly decreased NRF2 protein levels and increased oxidative stress, although (+)-PTZ did not disrupt NRF2-KEAP1 binding. In vivo studies were conducted to investigate whether, in the absence of NRF2, activation of Sig1R rescues cones. (+)-PTZ was administered systemically for several weeks to rd10/nrf2(+/+) and rd10/nrf2(-/-) mice. Through post-natal day 42, cone function was significant in rd10/nrf2(+/+), but minimal in rd10/nrf2(-/-) mice as indicated by electroretinographic recordings using natural noise stimuli, optical coherence tomography and retinal histological analyses. Immunodetection of cones was limited in (+)-PTZ-treated rd10/nrf2(-/-), though considerable in (+)-PTZ-treated rd10/nrf2(+/+)mice. The data suggest that Sig1R-mediated cone rescue requires NRF2 and provide evidence for a previously-unrecognized relationship between these proteins.
Wang, J., Zhao, J., Cui, X., Mysona, B., Navneet, S., Saul, A., Ahuja, M., Lambert, N., Gazaryan, I., Thomas, B., Bollinger, K., & Smith, S. (2019). The Molecular Chaperone Sigma 1 Receptor Mediates Rescue of Retinal Cone Photoreceptor Cells Via Modulation of NRF2. Free Radical Biology & Medicine, 134, 604-616. https://doi.org/10.1016/j.freeradbiomed.2019.02.001