Rods and cones coexist peacefully in healthy retinas. Both types of cell occupy the same layer of tissue and send signals when they detect light, which is the first step in vision. The incurable eye disease retinitis pigmentosa, however, reveals a codependent relationship between the two that can be destructive. When flawed rods begin to die, otherwise normal cones follow them to the grave, leading to blindness.
Researchers have proposed a variety of hypotheses to explain the loss of cones in patients with mutations in rod-specific genes, but it was not clear that these could explain all of the observations in patients and animal models of the disease. Howard Hughes investigator Constance Cepko, an HMS professor of genetics, took a fresh approach to the problem along with colleagues and published a new hypothesis in the January Nature Neuroscience.
Postdoctoral researcher Claudio Punzo gathered four strains of mice, each with a different rod-specific mutation and a different rate of disease progression. He discovered an interesting pattern—cone death always began after the major phase of rod death.
Punzo and collaborator Karl Kornacker, a professor at Ohio State University, analyzed gene expression before and after this point in each strain. During the cone death phase, 230 genes were always expressed at higher levels. Sleuthing revealed that 34.9 percent of these play a role in cellular metabolism, including 12 genes in the insulin/mTOR pathway.
mTOR serves as a signaling hub, gathering information about the environment and helping the cell decide whether it has enough nutrients to make new proteins. Punzo now had a lead. Further experiments suggested that the cones lacked nutrition. The cells revealed their problems when they were examined for evidence of self-digestion, or autophagy, a last ditch effort by the cell to survive a nutritional crisis by digesting its nonessential components. The cones appeared to be undergoing autophagy when the cone population was dying. To see if the self-digestion could be interrupted, Punzo tricked the cells into thinking they had enough nutrition by injecting the mice with insulin. Indeed, the death of cones was temporarily slowed.
Cepko said this nutrition hypothesis makes structural sense. Rods outnumber cones by more than 20 to 1, and retinal pigment epithelial (RPE) cells, which touch the photoreceptors and supply them with nutrients, probably sag when too many rods disappear. The structural change likely disturbs the contacts between RPE cells and cones, possibly impeding the flow of nutrients.
“This points us in a new direction,” said Cepko. “We’re currently exploring ways to boost nutrient levels in the cones.”
Cepko’s team is searching for other ways, as well, to boost photoreceptor survival. In a study published in the Jan. 9 issue of Science, postdoctoral researcher Bo Chen applied electroporation to show that he could keep rods and cones alive in mice with retinal disease by overexpressing the gene HDAC4. Chen injected DNA coding for HDAC4 into the retinas of newborn mice and administered an electric current to force the DNA into the cells. The mice with extra copies of the gene retained their rods and cones longer than mice without the extra copies. HDAC4 may protect the cells by stabilizing HIF1alpha, which regulates oxygen homeostasis.
Students may contact Constance Cepko at cepko@genetics.med.harvard.edu for more information.
Conflict Disclosure: The authors report no conflicts of interest.
Funding Sources: National Institutes of Health, the Macular Vision Research Foundation, the Foundation for Retinal Research, the Howard Hughes Medical Institute, Merck, and an EMBO fellowship
