"Professor Cho Won-gil’s Research Team Finds Novel Mechanism of eye disease"
The RPE is a monolayer of cells that provides nutrients to and shuttles waste away from the neighboring retina. In ~9% of individuals between the ages of 66 and 74, the central, or “macular,” RPE begins to break down, which eventually damages retinal photoreceptors and causes an incurable form of age-related macular degeneration known as “dry” AMD or geography atrophy. Prof. Cho and colleagues uncover an unexpected cause of this common disease: reduced levels of DICER1, the ribonuclease that is required for silencing genes by RnA interference. The study begins with the interesting observation that DICER1 mRnA is ~60% lower in the RPE of eyes with AMD compared to healthy eyes or those with other eye diseases. Indeed, when Kaneko et al. decrease the expression of Dicer1 in only the RPE of mice, the RPE cells degenerate. However, when they disrupt other components of the RnA interference machinery, such as Drosha and Ago, they see no changes, suggesting that Dicer’s effect on RPE cells is not simply due to a general disruption of RnA processing. Instead, Prof. Cho and colleagues find that a specific type of RnA accumulates in the AMD eyes: the transcripts from Alu retrotransposon elements, the most abundant repetitive sequences in the human genome. Injecting long Alu strands into mice retina induces RPE degeneration, but when the RnA is first digested with Dicer1, the RPE cells stay healthy. Together, these results indicate that decreased DICER1 levels trigger the accumulation of cytotoxic Alu RnA, which leads to RPE cell death and “dry” AMD. Interestingly, reduced DICER1 activity is connected to numerous diseases outside of the eye, hinting that this Alu-mediated mechanism of cytotoxicity may be “more than meets the eye.” The team further identified downstream molecules which mediate cytotoxicity of Alu RnAs such as nLRP3, PYCARD, IL-18 & other molecules that have critical function in inflammasome activation. In GA, the abundance of Dicer1 is reduced which leads to accumulation of cytotoxic Alu RnAs and RPE degeneration. This work will serve as the foundation for the rational design of therapeutics for treating this pervasive disease.