Zong-Yi Li

Apoptosis in Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of inherited retinal diseases characterized by progressive death of photoreceptors. Photoreceptor death in several rodent models of human RP was recently demonstrated to involve apoptosis. We sought to determine if photoreceptor death occurs by apoptosis in retinas from patients with RP. Donor retinas were screened using two labeling methods for in situ demonstration of fragmented nuclear DNA, a hallmark of apoptosis. To improve the sampling, portions of the retinas were processed as flat mounts. We examined 15 retinas from patients (age 24 to 87 yrs) who had different genetic forms of RP and retained photoreceptors at the time of death, as well as seven retinas from normal donors (age 19 to 68 yrs). Scattered labeled nuclei were present in the retinas from two RP donors who were 24 and 29 yrs old at the time of death. Labeled nuclei were not found in the normal retinas or in the retinas from the older RP donors. This study provides initial evidence that photoreceptor death in human RP occurs by apoptosis, as found previously in the rodent inherited retinal dystrophies. Apoptosis is a relatively rapid process in other types of cells, and it may be difficult to demonstrate in human RP retinas, where photoreceptor death is protracted over several decades. In addition, the likelihood of documenting this rather brief event in the retinas of older RP donors is small because they contain greatly reduced numbers of photoreceptors. Photoreceptor dysfunction results from several different gene defects in animal models and RP patients, but photoreceptor death in each case appears to occur by the final common pathway of apoptosis. Agents to inhibit apoptosis warrant evaluation as new therapy for inherited photoreceptor diseases.

A gradient of basic fibroblast growth factor in rod photoreceptors in the normal human retina

Retinitis pigmentosa (RP) is an inherited disease that causes primary degeneration of rod photoreceptors in the retina. Although the causal gene (e.g. rhodopsin) is thought to be expressed in all rods across the retina, the degeneration is typically nonuniform, with rods in the far periphery surviving significantly longer than those in the midperiphery and macula. Basic fibroblast growth factor (bFGF) is a putative survival factor for photoreceptors, and the characteristic regional pattern of rod cell survival in RP suggested that bFGF might be distributed nonuniformly in the human retina. We performed double-label immunocytochemistry on 15 normal human retinas, using anti-bFGF and other antibody markers for retinal neurons and glia. Immunoreactivity for bFGF was consistently absent from cones but was present in rods, populations of cone bipolar and amacrine cells, Müller glial cells, and astrocytes. In the macula, the percentage of bFGF-reactive rods was very low (approximately 0.5%) but it increased in a central to peripheral gradient, accounting for up to approximately 88% of the rods in the far periphery. These findings suggest that a central to peripheral gradient of rod bFGF is present in normal human retina and may influence the pattern of photoreceptor degeneration in RP. The absence of bFGF in cones and the low number of bFGF-positive rods in the macula may correlate with the vulnerability of these cells in RP, age-related macular degeneration, and other retinal diseases.

Retinal Pathology in Retinitis Pigmentosa

Retinitis pigmentosa (RP) causes primary degeneration of photoreceptors, followed by reactive changes in the retinal pigment epithelium (RPE) and Muller glia, death of inner retinal neurons, and atrophy of the retinal vasculature. Current strategies for retinal therapy include transplantation of normal photoreceptors, delivery of corrective genes to diseased photoreceptors, and electrical stimulation of inner retinal neurons [1–5]. This chapter will review the histopathology of the retina in RP, including the characteristic changes found in the photoreceptors, subretinal space, RPE and choriocapillaris, Muller glia, inner retinal neurons and blood vessels. Changes in these retinal components secondary to death of photoreceptors are important considerations in developing new therapies for RP