DICER1 in the Pathogenesis of Age-related Macular Degeneration (AMD) - Alu RNA Accumulation versus miRNA Dysregulation
Kai Kaarniranta1, Elzbieta Pawlowska2, Joanna Szczepanska3, Janusz Blasiak4,*
1Department of Ophthalmology, University of Eastern Finland, Kuopio 70211, Finland and Department of Ophthalmology, Kuopio University Hospital, Kuopio 70029, Finland. 2Department of Orthodontics, Medical University of Lodz, 92-216 Lodz, Poland. 3Department of Pediatric Dentistry, Medical University of Lodz, 92-216 Lodz, Poland. 4Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland.
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 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 mitochondrial 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.
Kai Kaarniranta,Elzbieta Pawlowska,Joanna Szczepanska, et al. DICER1 in the Pathogenesis of Age-related Macular Degeneration (AMD) - Alu RNA Accumulation versus miRNA Dysregulation[J]. Aging and disease,
Figure 1. Color fundus photograph (left) and fundus autofluorescence (FAF, right) of a patient with geographic atrophy (GA), an advanced form of age-related macular degeneration. Arrows indicate GA lesions with irreversibly damaged photoreceptors and retinal pigment epithelial cells. Increased FAF is detected around GA lesions.
Figure 2. Involvement of the DICER1 ribonuclease in the pathogenesis of geographic atrophy (GA), an incurable form of age-related macular degeneration (AMD). RNAs accumulate in animals with an inbred DICER1 deficiency as well as in human retinal pigment epithelium (RPE) cells with DICER1 knockout, and there is a global dysregulation of miRNAs. The same outcome can be observed when DICER1 is affected by oxidative stress. Independently of miRNA dysregulation, Alu RNAs accumulation can lead to RPE degeneration if this is inhibited by antisense oligonucleotides to Alu RNAs. Degeneration of RPE may be associated with the form of geographic atrophy (GA), an incurable type of age-related macular degeneration.
Figure 3. The accumulation of Alu RNAs leads to inflammasome formation and activation of interleukin 18 (IL-18) both of which may contribute to geographic atrophy (GA). DICER1 deficiency results in an excess of Alu RNAs; these induce oxidative stress and increase the production of reactive oxygen species (ROS). Subsequently, ROS prime the mRNA of NLRP3 (NACHT, LRR and PYD domains-containing protein 3) and IL18. NLRP3 associates with PYCARD and procaspase 1 to form the NLRP3 inflammasome that converts pre-interleukin 8 into its mature form, which in turn, mediates the activation of IRAK 1 and IRAK4 (interleukin-1 receptor-associated kinase 1 and 4) that contribute to RPE cells death, RPE degeneration and eventually GA.
Figure 4. Impairment in DICER1 in the retina may result in the accumulation of Alu transcripts and disturbances in miRNA biogenesis. Alu RNAs can induce mitochondrial dysfunction in retinal pigment epithelium (RPE) leading to excessive ROS production resulting in NLRP3 inflammasome activation and caspase-1 maturation, which can increase mitochondrial damage. NLRP3 activation is associated with the production of many intermediates and eventually leads to RPE cells degradation and death. Disturbed miRNA biogenesis can result in the deregulation of expression of many genes involved in retinal homeostasis in both RPE and neural retina and the miR-183/96/182 cluster belongs to the most important elements of that regulation, but as far as we are aware, all aspects of miRNA regulation in the retina are still far from clear. Only some aspects of dysregulated miRNAs in the neural retina are presented.
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