Cellular mechanisms of hereditary photoreceptor degeneration – Focus on cGMP |
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Institution: | 1. Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA;2. Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA;3. David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Ave., Los Angeles, CA 90095, USA;1. Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA;2. John A. Moran Eye Center, University of Utah, Salt Lake City, UT, USA;3. Zilkha Neurogenetic Institute, Department of Physiology and Neuroscience, University of Southern California Keck School of Medicine, Los Angeles, CA, USA;1. PhD Program in Neuroscience, Universidad de Valparaíso, Valparaíso, Chile;2. CINV, Instituto de Biología, Universidad de Valparaíso, Chile;3. Institute for Ophthalmic Research, University of Tübingen, Germany |
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Abstract: | The cellular mechanisms underlying hereditary photoreceptor degeneration are still poorly understood, a problem that is exacerbated by the enormous genetic heterogeneity of this disease group. However, the last decade has yielded a wealth of new knowledge on degenerative pathways and their diversity. Notably, a central role of cGMP-signalling has surfaced for photoreceptor cell death triggered by a subset of disease-causing mutations.In this review, we examine key aspects relevant for photoreceptor degeneration of hereditary origin. The topics covered include energy metabolism, epigenetics, protein quality control, as well as cGMP- and Ca2+-signalling, and how the related molecular and metabolic processes may trigger photoreceptor demise. We compare and integrate evidence on different cell death mechanisms that have been associated with photoreceptor degeneration, including apoptosis, necrosis, necroptosis, and PARthanatos. A special focus is then put on the mechanisms of cGMP-dependent cell death and how exceedingly high photoreceptor cGMP levels may cause activation of Ca2+-dependent calpain-type proteases, histone deacetylases and poly-ADP-ribose polymerase. An evaluation of the available literature reveals that a large group of patients suffering from hereditary photoreceptor degeneration carry mutations that are likely to trigger cGMP-dependent cell death, making this pathway a prime target for future therapy development.Finally, an outlook is given into technological and methodological developments that will with time likely contribute to a comprehensive overview over the entire metabolic complexity of photoreceptor cell death. Building on such developments, new imaging technology and novel biomarkers may be used to develop clinical test strategies, that fully consider the genetic heterogeneity of hereditary retinal degenerations, in order to facilitate clinical testing of novel treatment approaches. |
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Keywords: | cGMP Apoptosis PARthanatos Necroptosis PKG Raman microscopy |
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