Vertebrate sight and human visual health depend upon the dynamic architecture of rod and cone photore- ceptor outer segments (OSs). A broad variety of sight-robbing diseases is associated with defects in OS architecture;however, neither the underlying disease etiology, nor the fundamental biology of the receptor cells is well understood. Although speculative models for OS morphogenesis and scaffolding have been proposed, the molecular mechanisms responsible for organizing this organelle are not known. To address this knowledge gap, the long-term goal of this research is to define OS membrane architecture and renewal in sufficient detail to explain how defects in this organelle generate retinal disease. The current goal is to determine how peripherin-2/rds (P/rds) functions as an organizer for OS membranes. This integral mem- brane protein acts in an essential, though mechanistically uncertain (and differential) fashion to support OS architecture for both rods and cones. Inherited defects in P/rds cause a broad range of progressive dis- eases, including retinitis pigmentosa and macular degenerations.
The first Aim of this study will test the novel hypothesis that P/rds can function in trans to shape and tether OS disk rims via a hydrophobic inser- tion mechanism.
The second Aim will test the hypothesis that that P/rds self-assembly and/or heterotypic interactions can regulate activity for membrane curvature and/or tethering.
The third Aim will test the hy- pothesis that pathogenic mutations impair P/rds activity for membrane curvature generation and/or tether- ing. Completion of these aims would establish a new model for P/rds function and OS membrane organiza- tion. The work would also make a positive impact on the field by providing a new conceptual framework for rationalizing phenotype-genotype relationships for inherited defects in human P/rds and potentially manag- ing progressive retinal degenerations that result from primary pathologies in OS structure.

Public Health Relevance

Human sight relies on healthy rod and cone photoreceptor cells. These specialized neurons are fragile and can be harmed by inherited defects, environmental insults, and normal aging, to produce retinal degeneration and loss of vision. This research will improve understanding of healthy rod and cone cell structure and changes that occur during disease, and may suggest strategies for preserving sight.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Special Emphasis Panel (BVS)
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Neuhold, Lisa
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Oakland University
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Khattree, Nidhi; Ritter, Linda M; Goldberg, Andrew F X (2013) Membrane curvature generation by a C-terminal amphipathic helix in peripherin-2/rds, a tetraspanin required for photoreceptor sensory cilium morphogenesis. J Cell Sci 126:4659-70
Sharma, Yagya V; Cojocaru, Radu I; Ritter, Linda M et al. (2012) Protective gene expression changes elicited by an inherited defect in photoreceptor structure. PLoS One 7:e31371
Ritter, Linda M; Khattree, Nidhi; Tam, Beatrice et al. (2011) In situ visualization of protein interactions in sensory neurons: glutamic acid-rich proteins (GARPs) play differential roles for photoreceptor outer segment scaffolding. J Neurosci 31:11231-43
Kirschman, Lindsay T; Kolandaivelu, Saravanan; Frederick, Jeanne M et al. (2010) The Leber congenital amaurosis protein, AIPL1, is needed for the viability and functioning of cone photoreceptor cells. Hum Mol Genet 19:1076-87
Goldberg, Andrew F X; Ritter, Linda M; Khattree, Nidhi et al. (2007) An intramembrane glutamic acid governs peripherin/rds function for photoreceptor disk morphogenesis. Invest Ophthalmol Vis Sci 48:2975-86
Goldberg, Andrew F X (2006) Role of peripherin/rds in vertebrate photoreceptor architecture and inherited retinal degenerations. Int Rev Cytol 253:131-75
Ritter, L M; Arakawa, T; Goldberg, A F X (2005) Predicted and measured disorder in peripherin/rds, a retinal tetraspanin. Protein Pept Lett 12:677-86
Ding, Xi-Qin; Nour, May; Ritter, Linda M et al. (2004) The R172W mutation in peripherin/rds causes a cone-rod dystrophy in transgenic mice. Hum Mol Genet 13:2075-87
Ritter, Linda M; Boesze-Battaglia, Kathleen; Tam, Beatrice M et al. (2004) Uncoupling of photoreceptor peripherin/rds fusogenic activity from biosynthesis, subunit assembly, and targeting: a potential mechanism for pathogenic effects. J Biol Chem 279:39958-67
Boesze-Battaglia, Kathleen; Goldberg, Andrew F X; Dispoto, Janice et al. (2003) A soluble peripherin/Rds C-terminal polypeptide promotes membrane fusion and changes conformation upon membrane association. Exp Eye Res 77:505-14

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