Leber congenital amaurosis linked to AIPL1: A mouse model reveals destabilization of cGMP phosphodiesterase

Abstract

Leber congenital amaurosis (LCA4) has been linked to mutations in the photoreceptor-specific gene Aryl hydrocarbon interacting protein like 1 (Aipl1). To investigate the essential role of AIPL1 in retina, we generated a mouse model of LCA by inactivating the Aipl1 gene. In Aipl1 ؊/؊ retinas, the outer nuclear layer develops normally, but rods and cones then quickly degenerate. Aipl1 ؊/؊ mice have highly disorganized, short, fragmented photoreceptor outer segments and lack both rod and cone electroretinogram responses. Recent biochemical evidence indicates that AIPL1 can enhance protein farnesylation. Our study reveals that rod cGMP phosphodiesterase, a farnesylated protein, is absent and cGMP levels are elevated in AIPL1 ؊/؊ retinas before the onset of degeneration. Our findings demonstrate that AIPL1 enhances the stability of phosphodiesterase and is essential for photoreceptor viability. L eber congenital amaurosis (LCA) has the earliest onset and is the most severe form of inherited retinopathy in humans. LCA is genetically heterogeneous and is generally inherited in an autosomal recessive fashion. LCA is characterized by complete blindness and the near absence of electrical responses to light within 1 year of birth. LCA has been linked to mutations in the gene encoding Aipl1 (1-3). The vast majority of these mutations in Aipl1 are linked to LCA, but a few C-terminal mutations are linked to two other retinal diseases, cone-rod dystrophy and juvenile retinitis pigmentosa (3).AIPL1 is expressed only in retina and pineal gland (1). In adult mouse retina, it is found within the outer plexiform layer and the inner segments of photoreceptors; in humans, AIPL1 is expressed in both developing rods and cones and mature rods (4, 5). Two possibilities for the essential role for AIPL1 in retina have been proposed (4). The first is that AIPL1 enhances an essential farnesylation reaction. Farnesylation is a specific type of prenylation, the addition of a farnesyl or geranylgeranyl residue to specific proteins. Several retinal proteins, cGMP phosphodiesterase (PDE), transducin, and rhodopsin (Rho) kinase (RK) are known to be farnesylated (6-9). Prenylation of retinal proteins is required for maintenance of retinal cytoarchitecture and photoreceptor structure. Inhibition of prenylation causes degeneration of photoreceptor outer segments (10). Prenylation also greatly enhances the stability of cGMP PDE, a protein essential for photoreceptor survival (11). Prenylation of PDE is also necessary for its membrane association (11). These studies suggest that AIPL1 is necessary for the maintenance of photoreceptors. The second possible essential role for AIPL1 is the control of photoreceptor proliferation and or differentiation. AIPL1 interacts with Nedd8-ultimate buster 1 (NUB1), a ubiquitously expressed protein thought to play an important role in regulating cell cycle progression (12). Based on the NUB1 interaction, early expression of AIPL1 in human retina, and the severity of AIPL1 mutations linked to LCA, it has been proposed ...

Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina

“…Our findings that MCs do not express PK and that PRs express abundant PKM2 suggested that PRs, and not MCs, are the primary source of Lac. Retinas convert Glc to Lac at a very fast rate (4)(5)(6)(7)13 deficiency causes PR degeneration (27), so we extracted metabolites from mutant and control retinas and quantified them by GC/MS (Fig. S4).…”

Deletion of PrBP/δ impedes transport of GRK1 and PDE6 catalytic subunits to photoreceptor outer segments

“…A second prenyl binding protein candidate is aryl hydrocarbon receptor interacting protein-like 1 (AIPL1), which was shown to be involved in processing of farnesylated PDE6 (30). Knockout of AIPL1, linked to Leber Congenital Amaurosis in humans (31), results in rapid photoreceptor degeneration in the mouse (32). In Aipl1 Ϫ/Ϫ photoreceptors, newly synthesized PDE6 does not assemble correctly and is undetectable in ROS, which suggests a role for AIPL1 in chaperoning ER-docked PDE6 to transport carriers.…”

Interaction of Aryl Hydrocarbon Receptor-interacting Protein-like 1 with the Farnesyl Moiety

“…AIPL1 has been shown to interact with Nedd8 ultimate buster protein 1 (NUB1), implicated in cell cycle regulation and protein degradation (16). However, studies of AIPL1-deficient mouse models provided compelling evidence for phosphodiesterase 6 (PDE6) as the critical photoreceptor partner of AIPL1 (17,18). AIPL1 knock-out mice exhibited rapid severe degeneration of photoreceptors and had no measurable electroretinograms (17).…”