Photoreceptor Disc Enclosure Is Tightly Controlled by Peripherin-2 Oligomerization

Abstract

Mutations in the PRPH2 gene encoding the photoreceptor-specific protein PRPH2 (also known as peripherin-2 or rds) cause a broad range of autosomal dominant retinal diseases. Most of these mutations affect the structure of the light-sensitive photoreceptor outer segment, which is composed of a stack of flattened "disc" membranes surrounded by the plasma membrane. The outer segment is renewed on a daily basis in a process whereby new discs are added at the outer segment base and old discs are shed at the outer segment tip. New discs are formed as serial membrane evaginations, which eventually enclose through a complex process of membrane remodeling (completely in rods and partially in cones). As disc enclosure proceeds, PRPH2 localizes to the rims of enclosed discs where it forms oligomers which fortify the highly curved membrane structure of these rims. In this study, we analyzed the outer segment phenotypes of mice of both sexes bearing a single copy of either the C150S or the Y141C PRPH2 mutation known to prevent or increase the degree of PRPH2 oligomerization, respectively. Strikingly, both mutations increased the number of newly forming, not-yet-enclosed discs, indicating that the precision of disc enclosure is regulated by PRPH2 oligomerization. Without tightly controlled enclosure, discs occasionally over-elongate and form large membranous "whorls" instead of disc stacks. These data show that the defects in outer segment structure arising from abnormal PRPH2 oligomerization are manifested at the stage of disc enclosure.

Prph2 knock-in mice recapitulate human central areolar choroidal dystrophy retinal degeneration and exhibit aberrant synaptic remodeling and microglial activation

“…PRPH2 encodes the glycoprotein peripherin-2 (PRPH2), also known as retinal degeneration slow (RDS) protein, or tetraspanin-22 [ 6 ]. PRPH2 is essential for the morphogenesis and structure of the outer segment (OS) discs of photoreceptor cells [ 7 ]. CACD presents high genetic heterogeneity [ 8 ], and at least five different mutations in PRPH2 have been histologically and functionally described as causing this disease [ 3 , 4 , 9 – 13 ].…”

Photoreceptor disc incisures form as an adaptive mechanism ensuring the completion of disc enclosure

“…Such a pathology is observed in photoreceptors with a reduced molar ratio of peripherin-2 to rhodopsin, such as in rds/+ mice (Hawkins et al, 1985;Sanyal and Hawkins, 1986) and in mice overexpressing rhodopsin (Price et al, 2012). The same pathology is caused by mutations in peripherin-2 that affect its oligomerization (Stuck et al, 2014;Zulliger et al, 2018;Conley et al, 2019;Milstein et al, 2020;Lewis et al, 2021). Unlike peripherin-2 deficiency, an excess of peripherin-2 does not lead to severe morphological outer segment defects, such as in Rho +/mice or mice overexpressing peripherin-2 (Nour et al, 2004).…”

Prph2 mutant knock-in mice recapitulate all features of human central areolar choroidal dystrophy and reveals an aberrant synaptic remodelling and microglial activation

“…This gene is exclusively expressed in photoreceptor cells, and mice homozygous for rds show abnormal photoreceptor morphology and slow degeneration (Travis et al, 1991). PRPH2 controls the precision of disc morphology, as it is key for the formation and organization of the discs (Lewis et al, 2021). PRPH2 forms non-covalent homodimers and heterodimers, by interacting with rod outer segment membrane protein 1 (ROM-1), in a head-to-head assembly.…”

“…PRPH2 codi es the glycoprotein peripherin-2 (PRPH2), also known as retinal degeneration slow (RDS) protein, or tetraspanin-22 (Uniprot). PRPH2 is essential for the morphogenesis and structure of the outer segment (OS) discs of photoreceptor cells (Lewis et al, 2021). CACD presents a high genetic heterogeneity (Peeters et al, 2021), and at least ve different mutations in PRPH2 have been histologically and functionally described as causing this disease (Boon et al, 2009;Hoyng and Deutman, 1996; Keilhauer et al, 2006a;Nakazawa et al, 1995;Piguet et al, 1996;Wroblewski et al, 1994;Yanagihashi et al, 2003).…”