Author ORCID Identifier

https://orcid.org/0000-0002-0756-5421

Semester

Summer

Date of Graduation

2025

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Biochemistry

Committee Chair

Michael Robichaux

Committee Member

Visvanathan Ramamurthy

Committee Member

Michael Schaller

Committee Member

Martin Hruska

Committee Member

Wen-Tao Deng

Committee Member

Saravanan Kolandaivelu

Abstract

Rod photoreceptors are specialized neurons located in the retina, the neural tissue that lines the back of the eye. Rod photoreceptors are necessary for dim light and peripheral vision through the photoactivation rhodopsin (Rho). Rho is synthesized in the inner segment of rods before being unidirectionally trafficked to the outer segment. In diseases such as retinitis pigmentosa (RP), Rho trafficking can be disrupted, leading to progressive rod cell death. In many cases of RP, Rho is mislocalized to the rod photoreceptor synapse (“spherule”). The impact of Rho mislocalization on spherule structure and protein organization is poorly understood. We hypothesize that in mutant RP rods, Rho mislocalization to the spherules disrupts the normal secretory system for synaptic proteins, leading to localized presynaptic defects. Using a combination of super-resolution microscopy, transmission electron microscopy (TEM), and proteomics, we performed an in-depth analysis to test our hypothesis and determine how Rho mislocalization impacts spherule morphology and protein trafficking. Super-resolution imaging revealed differences in synaptic mislocalization and synaptic protein changes in a RP model for the P23H-Rho mutation, in which misfolded P23H-Rho protein accumulates in the rod’s endoplasmic reticulum (ER). Taken together, our data suggests an ER secretory system used by rods to supply their synaptic terminals that can be disrupted by misfolded P23H-Rho.

Download

Share

COinS