PRCD is Concentrated at the Base of Photoreceptor Outer Segments and is Involved in Outer Segment Disc Formation

Abstract

Mutations of the PRCD gene are associated with rod-cone degeneration in both dogs and humans. Prcd is expressed in the mouse eye as early as embryonic day 14. In the adult mouse retina PRCD is expressed in the outer segments of both rod and cone photoreceptors. Immunoelectron microscopy revealed that PRCD is located at the outer segment rim, and that it is highly concentrated at the base of the outer segment. Prcd-knockout mice present with progressive retinal degeneration, starting at 20 weeks of age and onwards. This process is reflected by a significant and progressive reduction of both scotopic and photopic electroretinographic responses, and by thinning of the retina, and specifically of the outer nuclear layer, indicating photoreceptor loss. Electron microscopy revealed severe damage to photoreceptor outer segments, which is associated with immigration of microglia cells to the Prcd-knockout retina, and accumulation of vesicles in the inter-photoreceptor space. Phagocytosis of photoreceptor outer segment discs by the retinal pigmented epithelium is severely reduced. Our data show that Prcd-knockout mice serve as a good model for retinal degeneration caused by PRCD mutations in humans. Our findings in these mice support the involvement of PRCD in outer segment disc formation of both rod and cone photoreceptors. Furthermore, they suggest a feedback mechanism which coordinates the rate of photoreceptor outer segment disc formation, shedding and phagocytosis. This study has important implications for understanding the function of PRCD in the retina, as well as for future development of treatment modalities for PRCD-deficiency in humans.

Loss of PRCD alters number and packaging density of rhodopsin in rod photoreceptor disc membranes

“…The most common PRCD mutation (C2Y) has been extensively characterized in several dog breeds 16 . Recent studies in additional mouse models have shown that high fidelity disc morphogenesis is compromised when PRCD is not present 34,35 . However, the precise role PRCD plays in this process remains unclear.…”

“…Consequently, membrane bulges containing rhodopsin appear to separate into extracellular vesicles and accrue within the interphotoreceptor space 34 . A second PRCD knockout mouse model has also shown accumulation of these vesicles and observed a reduced rate of phagocytosis of OS discs by the retinal pigment epithelium (RPE) 35 . Along with evidence of retinal degeneration in these models and structural defects exacerbated by microglia recruitment to clear these vesicles, it is clear that PRCD is required for proper OS maintenance and disc morphogenesis; however further studies are needed to clarify the precise mechanistic role which PRCD plays in these processes.…”

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

“…PRCD, progressive rod-cone degeneration, is a rhodopsin-binding protein [109] that localizes to the OS disc rims [110]. Patients and canines with PRCD C2Y mutations have a slowly progressive form of rod-cone degeneration [111].…”

“…While activated microglia infiltrate the interphotoreceptor space to remove extracellular vesicles and debris, removal is insufficient and PRs undergo a very slow degeneration. Homozygous Prcd tm1Vya mice show only 36% ONL loss at 17 months [112] while in Prcd tm1(KOMP)Mbp homozygotes a similar loss is observed at 30 weeks of age [110]. Both models are knockout alleles that target the 5 end of Prcd but are on different genetic backgrounds.…”

Large Animal Models of Inherited Retinal Degenerations: A Review

“…Additional mutations also located in exon 1 of PRCD have been identified in RP patients [172,173]. Since the discovery of Prcd, a mouse knockout model has been generated and experiments have shown Prcd's involvement in photoreceptor disc formation and maintenance [174][175][176]. Studies in the PRCD dog showed an early ultrastructural change that may have resulted from this purported function.…”