Iron-induced RNA Stability and Toxicity in Geographic Atrophy

Geographic atrophy (GA) is the major cause of untreatable blindness due to macular degeneration in the world, affecting over 1 million Americans, and many millions more worldwide. The underlying molecular causes of degeneration of the retinal pigmented epithelium (RPE) in GA remain elusive, obstructing efforts to develop effective targeted therapies. I recently contributed to the discovery of an exciting, new molecular pathway involving accumulation of toxic Alu RNAs, which is both active in human GA and faithfully reproduces GA-like features in cellular and animal models. These toxic endogenous RNAs activate the NLRP3 inflammasome to induce robust RPE degeneration. Normally, Alu RNAs are processed by the enzyme Dicer which renders them innocuous, a process which is significantly impaired in GA. New preliminary studies have identified free cytosolic iron as a potent negative regulator of Alu RNA processing by Dicer. Excess iron in the RPE is also independently associated with AMD development. I hypothesize that iron buildup in AMD contributes to the accretion and toxicity of Alu RNA transcripts. To test this hypothesis, I will pursue the following Specific Aims: 1) Identify the mechanisms underlying iron-sensitive Alu RNA processing by Dicer; and 2) Determine whether iron chelation prevents Alu RNA-induced RPE toxicity.. Successful completion of these Aims will integrate two parallel disease-promoting paradigms thereby providing new insights into the mechanisms of GA, and confirm or refute a new mode-of-action for iron-based therapies for AMD.