Is there an integrative hub of RPE viability that coordinates the effect of multiple, redundant stressors? The activity of the enzyme DICER1 is sufficiently broad-reaching that it is an attractive candidate as a choreographer of retinal health and homeostasis (Figure 4). Specifically, the literature supports an emerging role for DICER1 in governing

RPE cell health and function via several mechanisms, including its influence on inflammation and global (coding and noncoding) RNA expression. DICER1, a ribonuclease, was specifically reduced in the RPE of GA patients (Kaneko et al., 2011); moreover, this LY2157299 pathological decrease in DICER1 was accompanied by the aberrant overabundance of the noncoding GW786034 nmr Alu RNA, which is toxic to RPE cells. In that study, Kaneko et al. (2011) also present a new disease model of GA: the genetic ablation or knockdown of DICER1 in the mouse RPE. The Alu RNAs that accumulate in DICER1 deficiency are transcribed from

Alu DNA sequences in the nuclear genome. Sometimes described as “genomic parasites,” these ∼300 nt DNA sequences constitute at least 11% of all genomic DNA ( Batzer and Deininger, 2002). Alus are retrotransposons, meaning they “jump” around the genome by (1) transcription, (2) reverse transcription, and (3) genomic integration at a new locus. The deleterious effect of Alu sequences is often ascribed to a single retrotransposition event; for example, an Alu sequence may insert into a critical gene, thereby disrupting gene function ( Belancio et al., 2008). However, the mechanism of Alu RNA-induced toxicity in GA appears to occur by a novel pathway. Recent work has identified an innate immune complex called the NLRP3 inflammasome as the response platform that mediates Alu RNA-induced

RPE cell death ( Tarallo et al., 2012). That study provided evidence of inflammasome activation in the RPE of human GA donor eyes, and showed that in experimental DICER1 deficit, Oxymatrine activation of the NLRP3 inflammasome by Alu RNA leads to RPE IL-18 secretion, which induces MyD88-dependent RPE cell death. This finding solidifies the central role of the RPE in AMD pathogenesis. Interestingly, to date, NLRP3 inflammasome activation is almost exclusively confined to immune cells, thereby presenting an identity crisis for the RPE, which can now be redefined, in part, in terms of its immune function. As the mechanism of Alu RNA toxicity continues to be refined, one question remains unresolved: why do Alu RNAs accumulate in the RPE of GA patients? Because DICER1 cleaves Alu RNA, it is reasonable to expect that DICER1 deficit precedes Alu RNA accumulation. Therefore, it is important to ask: why does DICER1 decrease in GA? Recent studies show that a variety of stresses can regulate DICER1 expression.