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

Autor:	Nagar S; Neuroscience and Aging Research Center and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037., Noveral SM; Neuroscience and Aging Research Center and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121.; Department of Neurosciences and Program in Biomedical Sciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093., Trudler D; Neuroscience and Aging Research Center and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121., Lopez KM; Neuroscience and Aging Research Center and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121., McKercher SR; Neuroscience and Aging Research Center and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121., Han X; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037., Yates JR 3rd; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037., Piña-Crespo JC; Neuroscience and Aging Research Center and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037., Nakanishi N; Neuroscience and Aging Research Center and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121., Satoh T; Neuroscience and Aging Research Center and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121.; Department of Anti-Aging Food Research, School of Bioscience and Biotechnology, Tokyo University of Technology, Tokyo 192-0982, Japan., Okamoto SI; Neuroscience and Aging Research Center and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121., Lipton SA; Neuroscience and Aging Research Center and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037; slipton@ucsd.edu.; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121.; Department of Neurosciences and Program in Biomedical Sciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 May 16; Vol. 114 (20), pp. E4048-E4056. Date of Electronic Publication: 2017 May 01.
DOI:	10.1073/pnas.1613067114
Abstrakt:	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. Competing Interests: Conflict of interest statement: The Sanford-Burnham Medical Research Institute (now called Sanford Burnham Prebys Medical Discovery Institute) filed a patent application for cytoprotection by congeners of carnosic acid with S.A.L. and T.S. as joint inventors.
Databáze:	MEDLINE
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