Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
 
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and disease    2020, Vol. 11 Issue (4) : 851-862     DOI: 10.14336/AD.2019.0809
Review |
DICER1 in the Pathogenesis of Age-related Macular Degeneration (AMD) - Alu RNA Accumulation versus miRNA Dysregulation
Kaarniranta Kai1, Pawlowska Elzbieta2, Szczepanska Joanna3, Blasiak Janusz4,*
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.
Download: PDF(723 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    
Abstract  

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 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.

Keywords age-related macular degeneration      DICER1      Alu repeats      miRNA regulation      NLRP3 inflammasome     
Corresponding Authors: Blasiak Janusz   
About author:

These authors contributed equally to this work.

Just Accepted Date: 08 October 2019   Issue Date: 30 July 2020
Service
E-mail this article
E-mail Alert
RSS
Articles by authors
Kaarniranta Kai
Pawlowska Elzbieta
Szczepanska Joanna
Blasiak Janusz
Cite this article:   
Kaarniranta Kai,Pawlowska Elzbieta,Szczepanska Joanna, et al. DICER1 in the Pathogenesis of Age-related Macular Degeneration (AMD) - Alu RNA Accumulation versus miRNA Dysregulation[J]. Aging and disease, 2020, 11(4): 851-862.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2019.0809     OR
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 IRAK1 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.
[1] Bhutto I, Lutty G (2012). Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex. Mol Aspects Med, 33:295-317.
[2] Chew EY, Clemons TE, Agron E, Sperduto RD, Sangiovanni JP, Davis MD, et al. (2014). Ten-year follow-up of age-related macular degeneration in the age-related eye disease study: AREDS report no. 36. JAMA Ophthalmol, 132:272-277.
[3] Fleckenstein M, Mitchell P, Freund KB, Sadda S, Holz FG, Brittain C, et al. (2018). The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology, 125:369-390.
[4] Hyttinen JM, Blasiak J, Niittykoski M, Kinnunen K, Kauppinen A, Salminen A, et al. (2017). DNA damage response and autophagy in the degeneration of retinal pigment epithelial cells-Implications for age-related macular degeneration (AMD). Ageing Res Rev, 36:64-77.
[5] Tan PL, Bowes Rickman C, Katsanis N (2016). AMD and the alternative complement pathway: genetics and functional implications. Hum Genomics, 10:23.
[6] Arslan J, Baird PN (2018). Changing vision: a review of pharmacogenetic studies for treatment response in age-related macular degeneration patients. Pharmacogenomics, 19:435-461.
[7] Moore NA, Bracha P, Hussain RM, Morral N, Ciulla TA (2017). Gene therapy for age-related macular degeneration. Expert Opin Biol Ther, 17:1235-1244.
[8] van Leeuwen EM, Emri E, Merle BMJ, Colijn JM, Kersten E, Cougnard-Gregoire A, et al. (2018). A new perspective on lipid research in age-related macular degeneration. Prog Retin Eye Res, 67:56-86.
[9] Blasiak J, Salminen A, Kaarniranta K (2013). Potential of epigenetic mechanisms in AMD pathology. Front Biosci (Schol Ed), 5:412-425.
[10] Gemenetzi M, Lotery AJ (2014). The role of epigenetics in age-related macular degeneration. Eye (Lond), 28:1407-1417.
[11] Hjelmeland LM. Dark matters in AMD genetics: epigenetics and stochasticity (2011). Invest Ophthalmol Vis Sci, 52:1622-1631.
[12] Oliver VF, Jaffe AE, Song J, Wang G, Zhang P, Branham KE, et al. (2015). Differential DNA methylation identified in the blood and retina of AMD patients. Epigenetics, 10:698-707.
[13] Natoli R, Fernando N (2018). MicroRNA as therapeutics for age-related macular degeneration. Adv Exp Med Biol, 1074:37-43.
[14] Kauppinen A, Paterno JJ, Blasiak J, Salminen A, Kaarniranta K (2016). Inflammation and its role in age-related macular degeneration. Cell Mol Life Sci, 73:1765-1786.
[15] Strowig T, Henao-Mejia J, Elinav E, Flavell R (2012). Inflammasomes in health and disease. Nature, 481:278-286.
[16] Sutterwala FS, Haasken S, Cassel SL (2014). Mechanism of NLRP3 inflammasome activation. Ann N Y Acad Sci, 1319:82-95.
[17] Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. (2009). Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol, 183:787-791.
[18] Tseng WA, Thein T, Kinnunen K, Lashkari K, Gregory MS, D'Amore PA, et al. (2013). NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci, 54:110-120.
[19] Tarallo V, Hirano Y, Gelfand BD, Dridi S, Kerur N, Kim Y, et al. (2012). DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell, 149:847-859.
[20] Filipowicz W, Jaskiewicz L, Kolb FA, Pillai RS (2005). Post-transcriptional gene silencing by siRNAs and miRNAs. Curr Opin Struct Biol, 15:331-341.
[21] Melo SA, Sugimoto H, O'Connell JT, Kato N, Villanueva A, Vidal A, et al. (2014). Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell, 26:707-721.
[22] Song MS, Rossi JJ (2017). Molecular mechanisms of Dicer: endonuclease and enzymatic activity. Biochem J, 474:1603-1618.
[23] Dewannieux M, Esnault C, Heidmann T (2003). LINE-mediated retrotransposition of marked Alu sequences. Nat Genet, 35:41-48.
[24] Haig D (2016). Transposable elements: Self-seekers of the germline, team-players of the soma. Bioessays, 38:1158-1166.
[25] Hasler J, Strub K (2006). Alu elements as regulators of gene expression. Nucleic Acids Res, 34:5491-5497.
[26] Lieberman PM (2016). Retrotransposon-derived p53 binding sites enhance telomere maintenance and genome protection. Bioessays, 38:943-949.
[27] Lee HE, Ayarpadikannan S, Kim HS (2015). Role of transposable elements in genomic rearrangement, evolution, gene regulation and epigenetics in primates. Genes Genet Syst, 90:245-257.
[28] Ayarpadikannan S, Kim HS (2014). The impact of transposable elements in genome evolution and genetic instability and their implications in various diseases. Genomics Inform, 12:98-104.
[29] Ayarpadikannan S, Lee HE, Han K, Kim HS (2015). Transposable element-driven transcript diversification and its relevance to genetic disorders. Gene, 558:187-194.
[30] Hueso M, Cruzado JM, Torras J, Navarro E (2018). ALUminating the path of atherosclerosis progression: Chaos theory suggests a role for Alu repeats in the development of atherosclerotic vascular disease. Int J Mol Sci, 19.
[31] Kim S, Cho CS, Han K, Lee J (2016). Structural variation of Alu element and human disease. Genomics Inform, 14:70-77.
[32] Kaneko H, Dridi S, Tarallo V, Gelfand BD, Fowler BJ, Cho WG, et al. (2011). DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature, 471:325-330.
[33] Kerur N, Hirano Y, Tarallo V, Fowler BJ, Bastos-Carvalho A, Yasuma T, et al. (2013). TLR-independent and P2X7-dependent signaling mediate Alu RNA-induced NLRP3 inflammasome activation in geographic atrophy. Invest Ophthalmol Vis Sci, 54:7395-7401.
[34] Fowler BJ, Gelfand BD, Kim Y, Kerur N, Tarallo V, Hirano Y, et al. (2014). Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science, 346:1000-1003.
[35] Dridi S, Hirano Y, Tarallo V, Kim Y, Fowler BJ, Ambati BK, et al. (2012). ERK1/2 activation is a therapeutic target in age-related macular degeneration. Proc Natl Acad Sci U S A, 109:13781-13786.
[36] Lu Z, Xu S (2006). ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life, 58:621-631.
[37] Sawe N, Steinberg G, Zhao H (2008). Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J Neurosci Res, 86:1659-1669.
[38] Kerur N, Fukuda S, Banerjee D, Kim Y, Fu D, Apicella I, et al. (2018). cGAS drives noncanonical-inflammasome activation in age-related macular degeneration. Nat Med, 24:50-61.
[39] Hahn P, Milam AH, Dunaief JL (2003). Maculas affected by age-related macular degeneration contain increased chelatable iron in the retinal pigment epithelium and Bruch's membrane. Arch Ophthalmol, 121:1099-1105.
[40] He X, Hahn P, Iacovelli J, Wong R, King C, Bhisitkul R, et al. (2007). Iron homeostasis and toxicity in retinal degeneration. Prog Retin Eye Res, 26:649-673.
[41] Gelfand BD, Wright CB, Kim Y, Yasuma T, Yasuma R, Li S, et al. (2015). Iron toxicity in the retina requires Alu RNA and the NLRP3 inflammasome. Cell Rep, 11:1686-1693.
[42] Kaarniranta K, Tokarz P, Koskela A, Paterno J, Blasiak J (2017). Autophagy regulates death of retinal pigment epithelium cells in age-related macular degeneration. Cell Biol Toxicol, 33:113-128.
[43] Kim Y, Tarallo V, Kerur N, Yasuma T, Gelfand BD, Bastos-Carvalho A, et al. (2014). DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration. Proc Natl Acad Sci U S A, 111:16082-16087.
[44] Macfarlane LA, Murphy PR (2010) MicroRNA: biogenesis, function and role in cancer. Curr Genomics, 11:537-561.
[45] Ryan DG, Oliveira-Fernandes M, Lavker RM (2006). MicroRNAs of the mammalian eye display distinct and overlapping tissue specificity. Mol Vis, 12:1175-1184.
[46] Georgi SA, Reh TA (2010). Dicer is required for the transition from early to late progenitor state in the developing mouse retina. J Neurosci, 30:4048-4061.
[47] Pinter R, Hindges R (2010). Perturbations of microRNA function in mouse dicer mutants produce retinal defects and lead to aberrant axon pathfinding at the optic chiasm. PLoS One, 5(4):e10021.
[48] Frank RN (2004). Diabetic retinopathy. N Engl J Med, 350:48-58.
[49] Shen J, Yang X, Xie B, Chen Y, Swaim M, Hackett SF, et al. (2008). MicroRNAs regulate ocular neovascularization. Mol Ther, 16:1208-1216.
[50] Berber P, Grassmann F, Kiel C, Weber BH (2017). An eye on age-related macular degeneration: the role of microRNAs in disease pathology. Mol Diagn Ther, 21:31-43.
[51] Busskamp V, Krol J, Nelidova D, Daum J, Szikra T, Tsuda B, et al. (2014). miRNAs 182 and 183 are necessary to maintain adult cone photoreceptor outer segments and visual function. Neuron, 83:586-600.
[52] Lumayag S, Haldin CE, Corbett NJ, Wahlin KJ, Cowan C, Turturro S, et al. (2013). Inactivation of the microRNA-183/96/182 cluster results in syndromic retinal degeneration. Proc Natl Acad Sci U S A, 110:E507-516.
[53] Zhu Q, Sun W, Okano K, Chen Y, Zhang N, Maeda T, et al. (2011). Sponge transgenic mouse model reveals important roles for the microRNA-183 (miR-183)/96/182 cluster in postmitotic photoreceptors of the retina. J Biol Chem, 286:31749-31760.
[54] Sundermeier TR, Zhang N, Vinberg F, Mustafi D, Kohno H, Golczak M, et al. DICER1 is essential for survival of postmitotic rod photoreceptor cells in mice. FASEB J. 2014;28(8):3780-91. Epub 2014/05/09. doi: . PubMed PMID: ; PubMed Central PMCID: .
doi: 10.1096/fj.14-254292 pmid: 24812086
[55] Sundermeier TR, Sakami S, Sahu B, Howell SJ, Gao S, Dong Z, et al. (2017). MicroRNA-processing enzymes are essential for survival and function of mature retinal pigmented epithelial cells in mice. J Biol Chem, 292:3366-3378.
[56] Liu CH, Wang Z, Sun Y, SanGiovanni JP, Chen J (2016). Retinal expression of small non-coding RNAs in a murine model of proliferative retinopathy. Sci Rep, 6:33947.
[57] Sanuki R, Onishi A, Koike C, Muramatsu R, Watanabe S, Muranishi Y, et al. (2011). miR-124a is required for hippocampal axogenesis and retinal cone survival through Lhx2 suppression. Nat Neurosci, 14:1125-1134.
[58] Damiani D, Alexander JJ, O'Rourke JR, McManus M, Jadhav AP, Cepko CL, et al. (2008). Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina. J Neurosci, 28:4878-4887.
[59] Hamdi HK, Reznik J, Castellon R, Atilano SR, Ong JM, Udar N, et al. (2002). Alu DNA polymorphism in ACE gene is protective for age-related macular degeneration. Biochem Biophys Res Commun, 295:668-672.
[60] Hamdi HK, Kenney C (2003). Age-related macular degeneration: a new viewpoint. Front Biosci, 8:e305-314.
[61] Chong YS, Mai CW, Leong CO, Wong LC (2018). Lutein improves cell viability and reduces Alu RNA accumulation in hydrogen peroxide challenged retinal pigment epithelial cells. Cutan Ocul Toxicol, 37:52-60.
[62] Koushan K, Rusovici R, Li W, Ferguson LR, Chalam KV (2013). The role of lutein in eye-related disease. Nutrients, 5:1823-1839.
[63] Yan Y, Salazar TE, Dominguez JM 2nd, Nguyen DV, Li Calzi S, Bhatwadekar AD, et al. (2013). Dicer expression exhibits a tissue-specific diurnal pattern that is lost during aging and in diabetes. PLoS One, 8:e80029.
[64] Allam R, Lawlor KE, Yu EC, Mildenhall AL, Moujalled DM, Lewis RS, et al. (2014). Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO Rep, 15:982-990.
[65] Yu J, Nagasu H, Murakami T, Hoang H, Broderick L, Hoffman HM, et al. (2014). Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc Natl Acad Sci U S A, 111:15514-15519.
[66] Blasiak J, Szaflik JP (2011). DNA damage and repair in age-related macular degeneration. Front Biosci (Landmark Ed), 16:1291-1301.
[67] Ferrington DA, Kapphahn RJ, Leary MM, Atilano SR, Terluk MR, Karunadharma P, et al. (2016). Increased retinal mtDNA damage in the CFH variant associated with age-related macular degeneration. Exp Eye Res, 145:269-277.
[68] Li M, Zauhar RJ, Grazal C, Curcio CA, DeAngelis MM, Stambolian D (2017). RNA expression in human retina. Hum Mol Genet, 26:R68-r74.
[69] Zhu B, Zhu W, Ye S, Luo D, Xu K, Wu Z, et al. (2017). Quantification of microRNAs in human aqueous humor by miRFLP assay. Exp Eye Res, 162:73-78.
[1] N. Nagineni Chandrasekharam, K. Kommineni Vijay, Ganjbaksh Nader, K. Nagineni Krishnasai, J. Hooks John, Detrick Barbara. Inflammatory Cytokines Induce Expression of Chemokines by Human Retinal Cells: Role in Chemokine Receptor Mediated Age-related Macular Degeneration[J]. Aging and disease, 2015, 6(6): 444-455.
[2] Chandrasekharam N. Nagineni,Raghavan Raju,Krishnasai K. Nagineni,Vijay K. Kommineni,Aswini Cherukuri,R. Krishnan Kutty,John J. Hooks,Barbara Detrick. Resveratrol Suppresses Expression of VEGF by Human Retinal Pigment Epithelial Cells: Potential Nutraceutical for Age-related Macular Degeneration[J]. Aging and Disease, 2014, 5(2): 88-100.
Viewed
Full text


Abstract

Cited

  Shared   
Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail: editorial@aginganddisease.org
Powered by Beijing Magtech Co. Ltd