Understanding the significance of the AIPL1:NUB1 interaction for photoreceptor homeostasis (360G-Wellcome-077929_Z_05_Z)
Mutations in the pineal- and photoreceptor-specific aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) gene cause a devastating disease characterized by congenital blindness called Leber congenital amaurosis (LCA). The molecular basis of disease in LCA caused by AIPL1 mutations is not understood. It has been suggested that AIPL1 may function as a chaperone for phosphodiesterase (PDE) and farnesylated proteins. However, mutations in PDE subunits themselves lead to retinitis pigmentosa (RP) and global defects in the processing of farnesylated proteins were not observed in AIPL1 animal models. We have shown that AIPL1 can modulate the nuclear translocation and inclusion formation of the NEDD8 ultimate buster protein 1 (NUB1) and that this activity is affected by certain pathogenic mutations. NUB1 associates with the proteasome and targets small ubiquitin-like protein (NEDD8 and FAT10) conjugated proteins for degradation, providing a functional link between AIPL1 and the proteasome. However, the role of NUB1 in the retina is unknown. The primary goals of this study are therefore i) to determine the molecular mechanisms involved in the AIPL1-mediated regulation of NUB1 nuclear translocation ii) to determine the effect of AIPL1 on NUB1-mediated proteasomal degradation and downstream targets of NUB1 and iii) to determine whether these mechanisms are involved in the processing of PDE and farnesylated proteins by AIPL1, potentially establishing a relational link between the various pathways thus far implicated in AIPL1 LCA. Through these investigations we will gain a better understanding of the molecular mechanisms of AIPL1 LCA, which may identify novel targets for therapeutic intervention.
£216,710 20 Oct 2005