It has been demonstrated that AIPL1 is specifically able to interact with and enhance the post-translational farnesylation of proteins in the retina (Ramamurthy et al., 2003). Protein prenylation facilitates protein-protein and protein-membrane interactions, and is important in the maintenance of retinal cytoarchitecture and photoreceptor structure. It was shown that the ability of AIPL1 to interact with and enhance the processing of farnesylated proteins was severely compromised by certain pathogenic mutations including M79T and the non-functional W278X. It was suggested that AIPL1 may interact with the C-terminal prenylation motif in the cytosol dependent on the presence of a farnesyl transferase and either protect the farnesylated protein form proteasomal degradation in the cytosol, facilitate targeting of the protein to the ER for further processing, or chaperone the farnesylated protein to the target membrane (Figure 65.1). The AIPL1 mutants A197P and C239R, which were partially defective in their ability to interact with and facilitate the processing of far-nesylated proteins, were functional with respect to their effect on NUB1. Another AIPL1 mutation, R302L, did not show any defect in protein farnesylation but was compromised in NUB1 function. Hence, the mechanisms of disease pathogenesis in patients with AIPL1 mutations may depend on the specific interacting partner and functional pathway affected.
Recently, mouse models of LCA with either complete or partial inactivation of AIPL1 expression have suggested that AIPL1 may also function as a potential chaperone for cGMP phosphodiesterase (PDE) (Figure 65.1) (Liu et al., 2004; Ramamurthy et al., 2004). In both models, normal retinal histology and morphological photoreceptor development were observed at birth, although no recordable photofunction could be detected in AIPL1-- mice and the photoresponse onset and recovery was delayed in the rod photoreceptors of the AIPL1 hypomorphic mutant. Photoreceptor degeneration proceeded rapidly shortly after birth in the absence of AIPL1 but was significantly slowed in the presence of reduced levels of AIPL1. In both mouse models, all three subunits of the cGMP PDE holoenzyme (a, b and g) were reduced by a post-transcriptional mechanism before the onset of photoreceptor degeneration, suggesting that AIPL1 was necessary for the biosynthesis, assembly, or stabilization of PDE to proteasomal degradation. The PDE-a subunit is farnesylated and mutations that block farnesylation cause degradation of PDE-a protein in cultured cells (Qin and Baehr, 1994). However, LCA is more severe than retinitis pigmentosa (RP) caused by mutations in the PDE subunits.
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