title: The Leber congenital amaurosis protein, AIPL1, is needed for the viability and functioning of cone photoreceptor cells.
abstract: Leber congenital amaurosis (LCA) caused by mutations in Aryl hydrocarbon receptor interacting protein like-1 (Aipl1) is a severe form of childhood blindness. At 4 weeks of age, a mouse model of LCA lacking AIPL1 exhibits complete degeneration of both rod and cone photoreceptors. Rod cell death occurs due to rapid destabilization of rod phosphodiesterase, an enzyme essential for rod survival and function. However, little is understood regarding the role of AIPL1 in cone photoreceptors. Cone degeneration observed in the absence of AIPL1 could be due to an indirect 'bystander effect' caused by rod photoreceptor death or a direct role for AIPL1 in cones. To understand the importance of AIPL1 in cone photoreceptor cells, we transgenically expressed hAIPL1 exclusively in the rod photoreceptors of the Aipl1(-/-) mouse. Transgenic expression of hAIPL1 restored rod morphology and the rod-derived electroretinogram response, but cone photoreceptors were non-functional in the absence of AIPL1. In addition, the cone photoreceptors degenerate, but at a slower rate compared with Aipl1(-/-) mice. This degeneration is linked to the highly reduced levels of cone PDE6 observed in the hAIPL1 transgenic mice. Our studies demonstrate that AIPL1 is needed for the proper functioning and survival of cone photoreceptors. However, rod photoreceptors also provide support that partially preserves cone photoreceptors from rapid death in the absence of AIPL1.
authors.affiliation: Center for Neuroscience, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia 26505, USA.
authors.forename: Lindsay T
authors.initials: LT
authors.lastname: Kirschman
authors.forename: Saravanan
authors.initials: S
authors.lastname: Kolandaivelu
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Frederick
authors.forename: Loan
authors.initials: L
authors.lastname: Dang
authors.forename: Andrew F X
authors.initials: AF
authors.lastname: Goldberg
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
authors.forename: Visvanathan
authors.initials: V
authors.lastname: Ramamurthy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death; D002470:Cell Survival; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000378:metabolism; D004795:Enzyme Stability; D005136:Eye Proteins; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D055503:Protein Multimerization; D017949:Retinal Cone Photoreceptor Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D019076:Transgenes / Q000235:genetics; D014785:Vision, Ocular
chemical_list: C403625:AIPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D005136:Eye Proteins; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6