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 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.