Vertebrate sight and human visual health depend upon the membranous architecture of rod and cone photoreceptor outer segments (OSs). A broad variety of sight-robbing diseases is associated with defects in OS architecture; however, neither the underlying disease etiologies, nor the fundamental biology of the receptor cells is well understood. In particular, the molecular mechanisms responsible for generating and stabilizing the structure of mature rod and cone OS disks are not yet known. The long-term goal of this research is to define OS architecture and renewal in sufficient detail to explain how defects generate retinal disease and design effective therapeutic strategies. The current goal is to determine how peripherin-2/rds (P/rds) functions as an organizer for OS membranes. This integral membrane tetraspanin acts in an essential, though mechanistically uncertain fashion to support OS architecture for both rods and cones, and inherited mutations in P/rds cause a broad range of progressive diseases, including retinitis pigmentosa and macular degenerations.
The first Aim of this study will determine the importance of known protein structural/regulatory determinants for P/rds induction of highly curved membranes.
The second Aim will test the hypothesis that the P/rds C-terminus is normally membrane associated via partitioning of an inducible amphipathic helix that can function to tether OS disk rims together.
The third Aim will test the hypothesis that pathogenic mutations in the P/rds C-terminal domain can preferentially impact cone photoreceptors. Successful completion of the work proposed would improve knowledge of P/rds protein structure-function, clarify how P/rds can generate high curvature membranes to form and stabilize OS disks, and would provide a mechanistic basis for understanding how pathogenic mutations in P/rds preferentially affect cone (vs. rod) photoreceptors. The work could also make a positive impact by suggesting new strategies for managing 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 the changes that occur during progressive retinal disease, and may suggest strategies for preserving sight.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY025291-02
Application #
9265859
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Neuhold, Lisa
Project Start
2016-05-01
Project End
2020-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Oakland University
Department
Type
Organized Research Units
DUNS #
041808262
City
Rochester
State
MI
Country
United States
Zip Code
48309
Dilan, Tanya L; Singh, Ratnesh K; Saravanan, Thamaraiselvi et al. (2018) Bardet-Biedl syndrome-8 (BBS8) protein is crucial for the development of outer segments in photoreceptor neurons. Hum Mol Genet 27:283-294
Moye, Abigail R; Singh, Ratnesh; Kimler, Victoria A et al. (2018) ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure. Mol Biol Cell 29:1590-1598
Wright, Zachary C; Loskutov, Yuriy; Murphy, Daniel et al. (2018) ADP-Ribosylation Factor-Like 2 (ARL2) regulates cilia stability and development of outer segments in rod photoreceptor neurons. Sci Rep 8:16967
Milstein, Michelle L; Kimler, Victoria A; Ghatak, Chiranjib et al. (2017) An inducible amphipathic helix within the intrinsically disordered C terminus can participate in membrane curvature generation by peripherin-2/rds. J Biol Chem 292:7850-7865
Molday, Robert S; Goldberg, Andrew F X (2017) Peripherin diverts ciliary ectosome release to photoreceptor disc morphogenesis. J Cell Biol 216:1227-1229
Goldberg, Andrew F X; Moritz, Orson L; Williams, David S (2016) Molecular basis for photoreceptor outer segment architecture. Prog Retin Eye Res 55:52-81