Molecular mechanisms of outer segment renewal

The National Eye Institute awarded The Research Foundation For The State University of New York $456,915 on September 1, 2026, under the Vision Research program (CFDA 93.867) to investigate molecular mechanisms of photoreceptor outer segment renewal, with performance at Syracuse, New York, through May 31, 2031.

The project uncovers fundamental molecular mechanisms underpinning the constant renewal of photoreceptor outer segments, a process critical for vision. Defects in outer segment renewal underlie many inherited retinal degenerative diseases that lead to complete blindness in humans. The research investigates how the outer segment's light-sensitive membrane material is shaped into flattened membrane discs, how these discs are structurally stabilized, and how their molecular composition is controlled. Dozens of new disc membranes are built daily at the base of each outer segment while an equal number of old discs are discarded from the tip. The project focuses on two outer segment proteins critical for these processes—PRCD and KIAA1549—both linked to retinitis pigmentosa in humans. Preliminary data show that in the absence of PRCD, newly forming discs delaminate and bleb as extracellular vesicles that accumulate in the interphotoreceptor space. The work addresses unanswered questions about how disc proteins and lipids pass through the connecting cilium and how the ciliary plasma membrane evaginates into large membrane protrusions that subsequently flatten into newly forming disc lamellae.

Abstract

Molecular mechanisms of outer segment renewal this proposal uncovers fundamental molecular mechanisms underpinning the constant renewal of photoreceptor outer segments - a never-ending process that is crucial for our vision. Defects in outer segment renewal underlie many inherited retinal degenerative diseases that lead to complete blindness in humans. Elucidating how outer segments are renewed at the molecular level is the key to developing novel therapies. Here, we investigate unanswered questions about how the outer segment's light sensitive membrane material is shaped into flattened membrane discs, how these discs are structurally stabilized and how their molecular composition is controlled. Every day, dozens of new disc membranes are built at the base of each outer segment and an equal number of old discs are discarded from the tip. The tremendous never-ending flux of disc proteins and lipids into the outer segment initially must pass through the narrow connecting cilium that physically links the newly forming discs and photoreceptor cell body. The connecting cilium also acts as a ciliary gate regulating protein entry into the discs. Once protein and membrane material pass through the connecting cilium, the ciliary plasma membrane evaginates into large membrane protrusions that subsequently flatten into newly forming disc lamellae. In this proposal, we elucidate molecular mechanisms that drive the flattening of the newly forming discs, their stabilization and how their content is regulated. We focus on two outer segment proteins critical for these processes, prcd and KIAA1549, both of which are linked to retinitis pigmentosa in humans. In aim 1, we investigate the role of the disc-specific protein prcd. Our preliminary data show that in the absence of prcd, the newly forming discs delaminate and bleb as extracellular vesicles, which accumulate in the interphotoreceptor space. We will address the molecular mechanism by which prcd supports the structure of newly forming discs as they protrude from the cilium. In aim 2, we focus on KIAA1549 and its role in disc formation. Our preliminary data include a newly generated KIAA1549-/- mouse and suggest this protein may participate in regulating protein flux into the disc membranes and/or in the structural connection that supports the ciliary pocket. Our proposed experiments leverage innovative biochemical, proteomics and advanced electron microscopy techniques to elucidate these basic molecular mechanisms. By discovering how discs are built and stabilized we will answer long-standing questions about how our vision works at the molecular level and provide new molecular entry points for treating retinal disease.