PARP activity is essential for retinal photoreceptor survival in the human homologous RhoI255del mouse model for autosomal dominant retinitis pigmentosa

Abstract

Retinitis Pigmentosa (RP) is a group of rare, inherited, neurodegenerative diseases of the retina that primarily affect rod photoreceptors. The initial loss of rods is followed by a secondary cone photoreceptor degeneration and eventually legal blindness. Despite several attempts, RP still remains essentially untreatable. In recent years, inhibition of poly(ADP-ribose)polymerase (PARP) has been proposed as a potential therapeutic strategy of autosomal-recessive RP, based on promising work in preclinical animal models. However, the effects of PARP inhibitors in autosomal-dominant RP are still largely unknown. Here, we employed a novel, human-homologous rhodopsin-mutant RhoI255del/+ mouse model for autosomal dominant RP to assess the impact of different PARP inhibitors on the progression of photoreceptor degeneration. The PARP inhibitors used -olaparib, saruparib, INO1001, and nicotinamide- target different PARP isoforms, and their potentially differential effects were evaluated in organotypic retinal explants cultivated under entirely defined conditions. Readouts comprised in situ activity assays for PARP and calpain-type proteases, the TUNEL assay for cell death, as well as immunostaining for activated calpain-2, activated caspase-3, rhodopsin, and cone arrestin-3. Unexpectedly, and in contrast to previous findings in animal models for recessive RP, all of the included PARP inhibitors led to a marked and dose-dependent rod photoreceptor toxicity in the RhoI255del model for dominant RP. Furthermore, this effect appeared to be independent of rhodopsin expression. On the other hand, both cone photoreceptors and inner retinal neurons were apparently unaffected by PARP inhibition. The present study thus demonstrates the importance of PARP activity for rod photoreceptor viability in a dominant rhodopsin mutant, highlights the need for a deeper understanding of the mechanisms underlying photoreceptor degeneration in different RP forms, and cautions against the indiscriminate use of PARP inhibitors for the treatment of RP.