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HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice
- Source :
- Cell Death and Differentiation, Digital.CSIC. Repositorio Institucional del CSIC, instname
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- 16 p.-7 fig.<br />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.<br />This work was supported by the ProRetina foundation,the Kerstan Foundation, Deutsche Forschungsgemeinschaft (DFGTR 1238/4-1), Swiss National Science Foundation (31003A_173008),BMBF (FKZ: 01EK1613E), and GC2018-098557-B-I00 from MCIU/AEI/FEDER, UE. RGS is a recipient of a JIN grant RTI2018-098990- J-I00 from MCIU, Spain.
- Subjects :
- 10018 Ophthalmology Clinic
MAPK/ERK pathway
Programmed cell death
genetic structures
610 Medicine & health
Biology
Article
Photoreceptor cell
1307 Cell Biology
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Retinitis pigmentosa
1312 Molecular Biology
medicine
Animals
Molecular Biology
030304 developmental biology
Mice, Inbred C3H
0303 health sciences
Autophagy
Retinal
Cell Biology
medicine.disease
Cone cell
ddc
3. Good health
Cell biology
Histone Deacetylase Inhibitors
Mice, Inbred C57BL
Disease Models, Animal
Neuroprotective Agents
medicine.anatomical_structure
Histone
Gene Expression Regulation
chemistry
Intravitreal Injections
Retinal Cone Photoreceptor Cells
biology.protein
sense organs
Neurological disorders
Retinitis Pigmentosa
030217 neurology & neurosurgery
Neuroscience
Subjects
Details
- ISSN :
- 14765403, 13509047, and 20180985
- Volume :
- 28
- Database :
- OpenAIRE
- Journal :
- Cell Death & Differentiation
- Accession number :
- edsair.doi.dedup.....2ae81d1df99d81f1545f349ee0bce2af