Ablation Of Raf-1 Kinase Inhibitory Protein (RKIP) Improves Photoreceptor Structure and Function in a Cep290-Mutant Mouse Model Of Severe Retinal Degeneration
Abstract
Purpose: Mutations in the CEP290 gene are a frequent cause of childhood blindness disorder, Leber congenital amaurosis (LCA). Not much is known about the mode of action of CEP290 in the retina. We previously showed that CEP290 interacts with RKIP and that RKIP protein is abnormally accumulated in rd16 (retinal degeneration 16) mouse, a model of Cep290- associated retinal degeneration. The purpose of this study is to evaluate the role of RKIP accumulation in mediating photoreceptor degeneration in the rd16 mouse. Methods: rd16/rd16:Rkip ko/Rkip ko double homozygous knock out mice were generated by breeding rd16 and Rkip ko mice (both on C57BL6/J background). Photoreceptor structure and function were evaluated by Histology, Transmission electron microscopy (TEM), Immunofluorescence microscopy and Electroretinography (ERG). Results: We detected improved photoreceptor structure in the double homozygous mutant mice compared to rd16 at postnatal day 18 (P18). In addition, Rhodopsin and M-opsin staining in Rd16 Rkip-/- mouse showed increased outer segment localization in the double mutant mice. Finally, ERG analysis showed 40% scotopic response recovery in Rd16 Rkip-/- from Rd16 mouse. Conclusions: We propose that accumulation of RKIP due to mutation in CEP290, although not the only pathway is a critical step in the pathogenesis of associated severe retinal degeneration. Altering RKIP levels may potentially be used in combination with other modalities as an approach for treating such disorders.DOI
10.13028/702y-q067Permanent Link to this Item
http://hdl.handle.net/20.500.14038/27909Notes
Abstract of poster presented at the 2014 UMass Center for Clinical and Translational Science Research Retreat, held on May 20, 2014 at the University of Massachusetts Medical School, Worcester, Mass.
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http://creativecommons.org/licenses/by-nc-sa/3.0/ae974a485f413a2113503eed53cd6c53
10.13028/702y-q067