HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice
Open Access
- 6 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 28 (4), 1317-1332
- https://doi.org/10.1038/s41418-020-00653-3
Abstract
Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially unaffected. Extensive rod loss in advanced stages of the disease triggers cone death by a mechanism that is still largely unknown. Here, we show that secondary cone cell death in animal models for RP is associated with increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at late stages of the disease, when the majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival in two mouse models for RP, affected by mutations in the phosphodiesterase 6b gene. Moreover, the surviving cones remained light-sensitive, leading to an improvement in visual function. RNA-seq analysis of protected cones demonstrated that HDAC inhibition initiated multi-level protection via regulation of different pro-survival pathways, including MAPK, PI3K-Akt, and autophagy. This study suggests a unique opportunity for targeted pharmacological protection of secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients even in advanced disease stages.Keywords
Funding Information
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_173008, 31003A_173008)
- Bundesministerium für Bildung und Forschung (FKZ: 01EK1613E, FKZ: 01EK1613E)
- MCIU/AEI/FEDER, U
- Kerstan Foundation
This publication has 78 references indexed in Scilit:
- p38 MAPK signaling acts upstream of LIF-dependent neuroprotection during photoreceptor degenerationCell Death & Disease, 2013
- Physiological clustering of visual channels in the mouse retinaJournal of Neurophysiology, 2011
- Paintomics: a web based tool for the joint visualization of transcriptomics and metabolomics dataBioinformatics, 2010
- Excessive HDAC activation is critical for neurodegeneration in the rd1 mouseCell Death & Disease, 2010
- HDAC4 Regulates Neuronal Survival in Normal and Diseased RetinasScience, 2009
- The many roles of histone deacetylases in development and physiology: implications for disease and therapyNature Reviews Genetics, 2009
- HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatmentProceedings of the National Academy of Sciences of the United States of America, 2008
- Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosaNature Neuroscience, 2008
- Light/dark Transition Test for MiceJournal of Visualized Experiments, 2006
- Antioxidants reduce cone cell death in a model of retinitis pigmentosaProceedings of the National Academy of Sciences of the United States of America, 2006