MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

• Published in: Proceedings of the National Academy of Sciences - PNAS 2017-05, Vol.114 (20), p.E4048-E4056
• Main Authors: Nagar, Saumya, Noveral, Sarah M., Trudler, Dorit, Lopez, Kevin M., McKercher, Scott R., Han, Xuemei, Yates, John R., Piña-Crespo, Juan C., Nakanishi, Nobuki, Satoh, Takumi, Okamoto, Shu-ichi, Lipton, Stuart A.
• Format: Article
• Language: English
• Subjects: Aberration; Activation; Age; Age related diseases; Animals; Antioxidants; Biological Sciences; Cell death; Damage; Disease Models, Animal; Diseases; Diterpenes, Abietane; Downstream effects; Drugs; Environmental factors; Gene expression; Haploinsufficiency; Injuries; Light; Light - adverse effects; Macular degeneration; Mathematical models; MEF2 Transcription Factors - genetics; Mice; Mortality; NF-E2-Related Factor 2 - metabolism; Oxidative Stress; Oxygen; Pathology; Photoreceptor Cells, Vertebrate - metabolism; Photoreceptors; PNAS Plus; Reactive oxygen species; Reactive Oxygen Species - metabolism; Retina; Retinal degeneration; Retinal Degeneration - etiology; Retinitis; Retinitis pigmentosa; Rodents; Survival; Transcription factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1613067114

Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d +/− retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of light-induced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration.