Sahaboglu Ayse, Sharif Alaa, Feng Lili, Secer Enver, Zrenner Eberhart, Paquet-Durand François
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Graduate Training Center of Neuroscience, Tuebingen, Germany.
PLoS One. 2017 Jul 19;12(7):e0181374. doi: 10.1371/journal.pone.0181374. eCollection 2017.
Peripherin (peripherin/rds) is a membrane-associated protein that plays a critical role in the morphogenesis of rod and cone photoreceptor outer segments. Mutations in the corresponding PRPH2 gene cause different types of retinal dystrophies characterized by a loss of photoreceptors. Over activation of poly-ADP-ribose polymerase (PARP) was previously shown to be involved in different animal models for hereditary retinal dystrophies. This includes the rd2 mouse, which suffers from a human homologous mutation in the PRPH2 gene. In the present study, we show that increased retinal PARP activity and poly-ADP-ribosylation of proteins occurs before the peak of rd2 photoreceptor degeneration. Inhibition of PARP activity with the well-characterized PARP inhibitor PJ34 decreased the levels of poly-ADP-ribosylation and photoreceptor cell death. These results suggest a causal involvement of PARP in photoreceptor degeneration caused by peripherin mutations and highlight the possibility to use PARP inhibition for the mutation-independent treatment of hereditary retinal dystrophies.
外周蛋白（外周蛋白/视网膜变性慢病毒）是一种与膜相关的蛋白质，在视杆和视锥光感受器外段的形态发生中起关键作用。相应的PRPH2基因突变会导致不同类型的视网膜营养不良，其特征是光感受器丧失。先前已表明，多聚ADP核糖聚合酶（PARP）的过度激活与遗传性视网膜营养不良的不同动物模型有关。这包括rd2小鼠，它在PRPH2基因中存在人类同源突变。在本研究中，我们表明视网膜PARP活性增加和蛋白质的多聚ADP核糖基化发生在rd2光感受器变性的峰值之前。用特征明确的PARP抑制剂PJ34抑制PARP活性可降低多聚ADP核糖基化水平和光感受器细胞死亡。这些结果表明PARP在由外周蛋白突变引起的光感受器变性中存在因果关系，并突出了使用PARP抑制进行遗传性视网膜营养不良的非突变依赖性治疗的可能性。
