DICER1 in the Pathogenesis of Age-related Macular Degeneration (AMD) - Alu RNA Accumulation versus miRNA Dysregulation

DICER1 deficiency in the retinal pigment epithelium (RPE) was associated with the accumulation of Alu transcripts and implicated in geographic atrophy (GA), a form of age-related macular degeneration (AMD), an eye disease leading to blindness in millions of people. Although the exact mechanism of this association is not fully known, the activation of the NLRP3 inflammasome, maturation of caspase-1 and disruption in mitochondria! homeostasis in RPE cells were shown as critical for it. DICER1 deficiency results in dysregulation of miRNAs and changes in the expression of many genes important for RPE homeostasis, which may also contribute to AMD. DICER1 deficiency can change the functions of the miR-183/96/182 cluster that regulates photoreceptors and their synaptic transmission. Aging, the main AMD risk factor, is associated with decreased expression of DICER1 and changes in its diurnal pattern that are not synchronized with circadian regulation in the retina. The initial insult inducing DICER1 deficiency in AMD may be oxidative stress, another major risk factor of AMD, but further studies on the role of deficient DICER1 in AMD pathogenesis and its therapeutic potential are needed.