Differential effects of HDAC inhibitors in the RhoI255d mouse model for autosomal dominant retinitis pigmentosa

Abstract

Retinitis Pigmentosa (RP) is an inherited neurodegenerative disease which leads to loss of retinal photoreceptors and blindness. Histone deacetylases (HDAC) were previously found to be involved in photoreceptor cell death, and HDAC inhibitors have shown protective effects in animal models for autosomal recessive RP. However, whether HDAC inhibitors can protect photoreceptors in autosomal dominant RP (ADRP) remains unclear. Here, we utilized the recently generated human homologous RhoI255d/+ ADRP mouse model to investigate degenerative mechanisms and the therapeutic potential of HDAC inhibitors. To visualize photoreceptor HDAC activity, we applied an in situ HDAC activity assay on post-natal (P) day 20 wild type (WT) and RhoI255d/+ retina. Treatment with the HDAC class I/II inhibitor Trichostatin A and the HDAC class III inhibitor nicotinamide (NAM) suggested that most HDAC activity detected in RhoI255d/+ photoreceptors was related to class I/II isoforms. The therapeutic potential of different HDAC inhibitors, targeting different HDAC isoforms, was evaluated on organotypic retinal explants cultured under completely controlled conditions. HDAC inhibitors tested included SAHA (Vorinostat), MPT0G211, ACY-957, and NAM. Readouts comprised the TUNEL assay, immunostaining for activated calpain-2 and caspase-3, cone arrestin-3, and bromodeoxyuridine (BrdU)-labeling. Among the compounds tested, MPT0G211, targeting predominantly cytoplasmic HDAC-6, exhibited the strongest protective effect on both rod and cone photoreceptors. Remarkably, ACY-957, inhibiting nuclear HDAC-1/-2, at higher concentration induced both photoreceptor cell death and cell proliferation. High levels of NAM, blocking mitochondrial and nuclear HDACs, caused selective rod cell death, without affecting cones. All HDAC inhibitors tested had no or only minor effects on neurons of the inner retina. Our study highlights the complexity of HDAC activity during photoreceptor neurodegeneration and cautions against the use of unspecific inhibitors. At the same time, it showcases important differences between rod and cone photoreceptors and suggests especially HDAC-6 as a potential target for future therapy development. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/666875v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@598681org.highwire.dtl.DTLVardef@18d8ba4org.highwire.dtl.DTLVardef@1cacb24org.highwire.dtl.DTLVardef@dec519_HPS_FORMAT_FIGEXP M_FIG C_FIG