Retinal degeneration and blindness, possibly preventable

Photo by Aaron (~Sayn)

Neurodegenerative diseases such as retinitis pigmentosa (RP) currently ravage through the eyes of millions of people worldwide unhindered and untreated. Genetic disorders like these often leave patients blind with no good news from the time of diagnosis. That is likely to change soon as researchers of the Universities of Toronto, Lausanne, Lund, and The Centre of Biomedical Genetics (Amsterdam) found Bmi1 and cyclin-dependent kinases (CDKs) a potential targets to prevent blindness caused by neurodegeneration.

Retinal pigmentosa results from the mutation of around 200 loci or genes leading to the loss of rod and cone photoreceptors. Previous studies showed that neurons prepared to die (due to a neurodegenerative disease) reexpress cell cycle-related proteins like CDKs. Specifically CDK4 and CDK6 activation was seen as involved with neuronal death in these conditions.

Bmi1 to E2F1 cycle

Bmi1 is a polycomb group protein (proteins that silence genes) which inhibits CDK inhibitors. These normally lessen the activity of CDK’s, which inhibit retinoblastoma (Rb) proteins. The Rb proteins down-regulate E2F1, which causes the cell to divide past it’s prime. This little cell cycle here has been shown to be the cause of neurodegeneration in Parkinson’s disease; therefore, researchers are investigating the effects of it in ophthalmological cases.

Rb1 mice (those with induced RP) were first analyzed for their expression of cell cycle markers. Between postnatal day nine (P9) and P12, the amount of CDK4/6 significantly increased in the apoptotic cells of the Rd1 mice. However, almost no CDK4/6 was detected in the wild type mice’s retinal cells.

Because of the higher expression seen, CDK interference was run. An ex vivo (pulled part of the retina out of the mouse to study) assay was performed with retinal explants of Rd1 mice. Using roscovitine (CDK inhibitor) vs. no treatment groups, photoreceptor degeneration was measured. The roscovitine group showed 42% less apoptotic photoreceptors. This meant CDK4/6 were contributing to the loss of photoreceptors.

Consistent with this, inhibited Rb1 was found in Rb1 mice and not wild type mice. This meant E2F proteins were allowed to freely push the cell into apoptotic division. Playing with alleles and expression patterns of E2F1,2,3 in combination, researchers were able to determine ESF1 was more important than E2F2/3 in neurodegeneration. Deleting the gene resulted in slowed, but not stopped photoreceptor degeneration.

Finally, Rd1/Bmi1-/- mice were analyzed vs. Rd1 mice to see the protective effect of removing Bmi1 all together. Respectively, 40% and 90% photoreceptor loss was seen in the mice. Rd1/Bmi1-/- mice lost 50% less photoreceptors than the normal retinitis pigmentosa mice.

Pulling all together, retinal degeneration was significantly slowed and prevented leading to a protection of photoreceptors by inhibition of Bmi1, CDK4/6, and E2F1. Being diagnosed with RP may not be as hopeless any longer. Once therapies are pushed into the clinic using the targets found in this study, RP patients may shrug at their diagnosis rather than shudder.

Dusan Zencak, Karine Schouwey, Danian Chen, Per Ekström, Ellen Tanger, Rod Bremner, Maarten van Lohuizen, Yvan Arsenijevic. Retinal degeneration depends on Bmi1 function and reactivation of cell cycle proteins. Proceedings of the National Academy of Sciences of the United States of America, 2013.


Asprin linked to vision loss

Credited as a stand alone complex popularized by Happy Wheels.

Headache puppy

A recent Wisconsin based study has just concluded after a 20 year longitudinal analysis was done over an adult cohort of 4,926 participants. The researchers were evaluating the association of regular aspirin use with incidence of age-related macular degeneration (AMD). It was found that aspirin may cause macular degeneration.

Human eye. Courtesy of St. Luke’s Cataract & Laser Institute

Macular degeneration is a process usually affecting older adults in which their macula, part of the retina that is the center of visual field and area responsible for sharpest day as well as color vision, is deprived of blood and degenerates. This can happen because either debris got in the area between retina and choroid, blood supply layer of the eye, or excess blood vessels grew in and detached the retina. It was hypothesized that long-term, regular aspirin use may contribute to the development of the later form of AMD.

Eye examinations were performed every five years for participants age 43-86. Patients were asked if they used aspirin regularly, defined as at least twice every week over three months. Aspirin use over a 10 year period was associated with late AMD, but not early. However, aspirin use over a 5 year period was not significantly associated with either type of AMD. A 14.8 year (average) followup showed 512 late AMD 117 early AMD cases. Specifically,

– 10 year use was associated with greater late AMD
— Hazard ratio (HR): 1.63, Confidence interval (CI): 95% from 1.01 to 2.63, P=0.05
— Regular user incidence of AMD: 1.76%, CI: 95% from 1.17% to 2.646%
— Non-user incidence of AMD: 1.03%, CI: 95% from 0.70% to 1.51%
– 10 year use was associated with greater late neovascular AMD
— HR: 2.20, CI: 95% from 1.20 to 4.15, P=0.01

Since nearly 20% of adults in the U.S. use aspirin regularly, these findings were significant for aspirin users and the ophthalmologists treating them. If the mechanisms behind this link are discovered, it can very well help treat or prevent vision loss due to late neovascular AMD and related conditions.

Barbara E. K. Klein, Kerri P. Howard, Ronald E. Gangnon, Jennifer O. Dreyer, Kristine E. Lee, Ronald Klein. 2012. Long-term Use of Aspirin and Age-Related Macular Degeneration. The Journal of the American Medical Association.