Luigi Donato, Concetta Scimone, Simona Alibrandi, Rosalia D’Angelo, Antonina Sidoti
Abstract
Retinitis pigmentosa is a heterogeneous eye disease group with a relatively high prevalence and a frequent onset at the middle age. Clinical observation of the wide spectrum of this pathology has been efficient, such as their genetic analysis, and a large catalogue of implicated loci has emerged. In addition to locus and allelic heterogeneity, along with allelic disorders, the complexity of retinitis pigmentosa is related to the actual lack of knowledge on all possible causative genes and their function. Such scenario implies that retinitis pigmentosa pathogenesis is not well understood, thus the research of new involved biochemical pathways is vital. In this review, we consider the architecture of genetic aspects that influence retinal degeneration, analyzing main biochemical pathways (such as inflammation, circadian rhythms, fatty acid metabolism, proteostasis, vesicular trafficking, phototransduction, RNA processing, extracellular matrix remodeling, cellular cycle regulation, etc.) implicated in photoreceptor degeneration via RPE impairments.
References
1. Muniz A BB, Trevino AR, Buddavarapu K, Roman R, Ma JX, Tsin AT. Evidence for two retinoid cycles in the cone-dominated chicken eye. Biochemistry 2009;48:6854-63.
2. PA C. Molecular pathogenesis of retinal and choroidal vascular diseases. Prog Retin Eye Res 2015;49:67-81.
3. Nguyen-Legros J HD. Renewal of photoreceptor outer segments and their phagocytosis by the retinal pigment epithelium. Int Rev Cytol 2000;196:245-313.
4. King GL SK. Pigment-epithelium-derived factor–a key coordinator of retinal neuronal and vascular functions. N Engl J Med 2000;342:349-51.
5. Beatty S MI, Henson DB, Carden D, Koh H, Boulton ME. Macular pigment and risk for age-related macular degeneration in subjects from a Northern European population. Invest Ophthalmol Vis Sci 2001;42:439-46.
6. Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations causing retinitis pigmentosa. Clin Genet 2013;84:132-41.
7. Patel N, Aldahmesh MA, Alkuraya H, Anazi S, Alsharif H, Khan AO, Sunker A, Al-Mohsen S, Abboud EB, Nowilaty SR, Alowain M, Al-Zaidan H, Al-Saud B, Alasmari A, Abdel-Salam GM, Abouelhoda M, Abdulwahab FM, Ibrahim N, Naim E, Al-Younes B, A EA, AlIssa A, Hashem M, Buzovetsky O, Xiong Y, Monies D, Altassan N, Shaheen R, Al-Hazzaa SA, Alkuraya FS. Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies. Genet Med 2016;18:554-62.
8. Brandstetter C, Patt J, Holz FG, Krohne TU. Inflammasome priming increases retinal pigment epithelial cell susceptibility to lipofuscin phototoxicity by changing the cell death mechanism from apoptosis to pyroptosis. J Photochem Photobiol B 2016;161:177-83.
9. Dick AD. Doyne lecture 2016: intraocular health and the many faces of inflammation. Eye (Lond) 2017;31:87-96.
10. Liu Y, Zhou J, Wang L, Hu X, Liu X, Liu M, Cao Z, Shangguan D, Tan W. A Cyanine Dye to Probe Mitophagy: Simultaneous Detection of Mitochondria and Autolysosomes in Live Cells. J Am Chem Soc 2016;138:12368-74.
11. Rohrer B, Bandyopadhyay M, Beeson C. Reduced Metabolic Capacity in Aged Primary Retinal Pigment Epithelium (RPE) is Correlated with Increased Susceptibility to Oxidative Stress. Adv Exp Med Biol 2016;854:793-8.
12. Matsunaga D, Sreekumar PG, Ishikawa K, Terasaki H, Barron E, Cohen P, Kannan R, Hinton DR. Humanin Protects RPE Cells from Endoplasmic Reticulum Stress-Induced Apoptosis by Upregulation of Mitochondrial Glutathione. PLoS One 2016;11:e0165150.
13. Chichagova V, Hallam D, Collin J, Buskin A, Saretzki G, Armstrong L, Yu-Wai-Man P, Lako M, Steel DH. Human iPSC disease modelling reveals functional and structural defects in retinal pigment epithelial cells harbouring the m.3243A > G mitochondrial DNA mutation. Sci Rep 2017;7:12320.
14. Pinelli M, Carissimo A, Cutillo L, Lai CH, Mutarelli M, Moretti MN, Singh MV, Karali M, Carrella D, Pizzo M, Russo F, Ferrari S, Ponzin D, Angelini C, Banfi S, di Bernardo D. An atlas of gene expression and gene co-regulation in the human retina. Nucleic Acids Res 2016;44:5773-84.
15. Schmidt-Kastner R, Yamamoto H, Hamasaki D, Yamamoto H, Parel JM, Schmitz C, Dorey CK, Blanks JC, Preising MN. Hypoxia-regulated components of the U4/U6.U5 tri-small nuclear riboprotein complex: possible role in autosomal dominant retinitis pigmentosa. Mol Vis 2008;14:125-35.
16. Besharse JC, McMahon DG. The Retina and Other Light-sensitive Ocular Clocks. J Biol Rhythms 2016;31:223-43.
17. Sethna S, Chamakkala T, Gu X, Thompson TC, Cao G, Elliott MH, Finnemann SC. Regulation of Phagolysosomal Digestion by Caveolin-1 of the Retinal Pigment Epithelium Is Essential for Vision. J Biol Chem 2016;291:6494-506.
18. Fanjul-Moles ML, Lopez-Riquelme GO. Relationship between Oxidative Stress, Circadian Rhythms, and AMD. Oxid Med Cell Longev 2016;2016:7420637.
19. Yao J, Jia L, Shelby SJ, Ganios AM, Feathers K, Thompson DA, Zacks DN. Circadian and noncircadian modulation of autophagy in photoreceptors and retinal pigment epithelium. Invest Ophthalmol Vis Sci 2014;55:3237-46.
20. Olchawa MM, Furso JA, Szewczyk GM, Sarna TJ. Lipofuscin-mediated photic stress inhibits phagocytic activity of ARPE-19 cells; effect of donors’ age and antioxidants. Free Radic Res 2017:1-13.
21. Laurent V, Sengupta A, Sanchez-Bretano A, Hicks D, Tosini G. Melatonin signaling affects the timing in the daily rhythm of phagocytic activity by the retinal pigment epithelium. Exp Eye Res 2017;165:90-95.
22. Hunter A, Spechler PA, Cwanger A, Song Y, Zhang Z, Ying GS, Hunter AK, Dezoeten E, Dunaief JL. DNA methylation is associated with altered gene expression in AMD. Invest Ophthalmol Vis Sci 2012;53:2089-105.
23. Alivand MR, Soheili ZS, Pornour M, Solali S, Sabouni F. Novel Epigenetic Controlling of Hypoxia Pathway Related to Overexpression and Promoter Hypomethylation of TET1 and TET2 in RPE Cells. J Cell Biochem 2017;118:3193-3204.
24. Amram B, Cohen-Tayar Y, David A, Ashery-Padan R. The retinal pigmented epithelium – from basic developmental biology research to translational approaches. Int J Dev Biol 2017;61:225-234.
25. Gong Y, Fu Z, Liegl R, Chen J, Hellstrom A, Smith LE. omega-3 and omega-6 long-chain PUFAs and their enzymatic metabolites in neovascular eye diseases. Am J Clin Nutr 2017;106:16-26.
26. Rice DS, Calandria JM, Gordon WC, Jun B, Zhou Y, Gelfman CM, Li S, Jin M, Knott EJ, Chang B, Abuin A, Issa T, Potter D, Platt KA, Bazan NG. Adiponectin receptor 1 conserves docosahexaenoic acid and promotes photoreceptor cell survival. Nat Commun 2015;6:6228.
27. Gorusupudi A, Liu A, Hageman GS, Bernstein PS. Associations of human retinal very long-chain polyunsaturated fatty acids with dietary lipid biomarkers. J Lipid Res 2016;57:499-508.
28. Azadi S, Brush RS, Anderson RE, Rajala RV. Class I Phosphoinositide 3-Kinase Exerts a Differential Role on Cell Survival and Cell Trafficking in Retina. Adv Exp Med Biol 2016;854:363-9.
29. Dutta N, Seo S. RPGR, a prenylated retinal ciliopathy protein, is targeted to cilia in a prenylation- and PDE6D-dependent manner. Biol Open 2016;5:1283-9.
30. Di Gioia SA, Farinelli P, Letteboer SJ, Arsenijevic Y, Sharon D, Roepman R, Rivolta C. Interactome analysis reveals that FAM161A, deficient in recessive retinitis pigmentosa, is a component of the Golgi-centrosomal network. Hum Mol Genet 2015;24:3359-71.
31. Schwarz N, Lane A, Jovanovic K, Parfitt DA, Aguila M, Thompson CL, da Cruz L, Coffey PJ, Chapple JP, Hardcastle AJ, Cheetham ME. Arl3 and RP2 regulate the trafficking of ciliary tip kinesins. Hum Mol Genet 2017;26:2480-2492.
32. Kabir F, Ullah I, Ali S, Gottsch AD, Naeem MA, Assir MZ, Khan SN, Akram J, Riazuddin S, Ayyagari R, Hejtmancik JF, Riazuddin SA. Loss of function mutations in RP1 are responsible for retinitis pigmentosa in consanguineous familial cases. Mol Vis 2016;22:610-25.
33. Lin JH, Lavail MM. Misfolded proteins and retinal dystrophies. Adv Exp Med Biol 2010;664:115-21.
34. Xie LS, Qin W, Fan JM, Huang J, Xie XS, Li Z. The role of C1GALT1C1 in lipopolysaccharide-induced IgA1 aberrant O-glycosylation in IgA nephropathy. Clin Invest Med 2010;33:E5-13.
35. Alpi AF, Chaugule V, Walden H. Mechanism and disease association of E2-conjugating enzymes: lessons from UBE2T and UBE2L3. Biochem J 2016;473:3401-3419.
36. Niikura Y, Kitagawa R, Ogi H, Kitagawa K. SGT1-HSP90 complex is required for CENP-A deposition at centromeres. Cell Cycle 2017;16:1683-1694.
37. Yang P, Skiba NP, Tewkesbury GM, Treboschi VM, Baciu P, Jaffe GJ. Complement-Mediated Regulation of Apolipoprotein E in Cultured Human RPE Cells. Invest Ophthalmol Vis Sci 2017;58:3073-3085.
38. Gaub BM, Berry MH, Holt AE, Reiner A, Kienzler MA, Dolgova N, Nikonov S, Aguirre GD, Beltran WA, Flannery JG, Isacoff EY. Restoration of visual function by expression of a light-gated mammalian ion channel in retinal ganglion cells or ON-bipolar cells. Proc Natl Acad Sci U S A 2014;111:E5574-83.
39. Luo R, Reed CE, Sload JA, Wordeman L, Randazzo PA, Chen PW. Arf GAPs and molecular motors. Small GTPases 2017:1-14.
40. Lee JJ, Seo S. PDE6D binds to the C-terminus of RPGR in a prenylation-dependent manner. EMBO Rep 2015;16:1581-2.
41. Nash BM, Wright DC, Grigg JR, Bennetts B, Jamieson RV. Retinal dystrophies, genomic applications in diagnosis and prospects for therapy. Transl Pediatr 2015;4:139-63.
42. Papal S, Cortese M, Legendre K, Sorusch N, Dragavon J, Sahly I, Shorte S, Wolfrum U, Petit C, El-Amraoui A. The giant spectrin betaV couples the molecular motors to phototransduction and Usher syndrome type I proteins along their trafficking route. Hum Mol Genet 2013;22:3773-88.
43. Fogerty J, Besharse JC. 174delG mutation in mouse MFRP causes photoreceptor degeneration and RPE atrophy. Invest Ophthalmol Vis Sci 2011;52:7256-66.
44. Sugitani K, Koriyama Y, Ogai K, Wakasugi K, Kato S. A Possible Role of Neuroglobin in the Retina After Optic Nerve Injury: A Comparative Study of Zebrafish and Mouse Retina. Adv Exp Med Biol 2016;854:671-5.
45. Li ZY, Kljavin IJ, Milam AH. Rod photoreceptor neurite sprouting in retinitis pigmentosa. J Neurosci 1995;15:5429-38.
46. Jensen RJ. Blocking GABA(C) receptors increases light responsiveness of retinal ganglion cells in a rat model of retinitis pigmentosa. Exp Eye Res 2012;105:21-6.
47. Karunakaran DK, Al Seesi S, Banday AR, Baumgartner M, Olthof A, Lemoine C, Mandoiu, II, Kanadia RN. Network-based bioinformatics analysis of spatio-temporal RNA-Seq data reveals transcriptional programs underpinning normal and aberrant retinal development. BMC Genomics 2016;17 Suppl 5:495.
48. Tanackovic G, Ransijn A, Thibault P, Abou Elela S, Klinck R, Berson EL, Chabot B, Rivolta C. PRPF mutations are associated with generalized defects in spliceosome formation and pre-mRNA splicing in patients with retinitis pigmentosa. Hum Mol Genet 2011;20:2116-30.
49. Shinde V, Kotla P, Strang C, Gorbatyuk M. Unfolded protein response-induced dysregulation of calcium homeostasis promotes retinal degeneration in rat models of autosomal dominant retinitis pigmentosa. Cell Death Dis 2016;7:e2085.
50. Hiramatsu N, Chiang WC, Kurt TD, Sigurdson CJ, Lin JH. Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death. Am J Pathol 2015;185:1800-8.
51. Esposito G, Testa F, Zacchia M, Crispo AA, Di Iorio V, Capolongo G, Rinaldi L, D’Antonio M, Fioretti T, Iadicicco P, Rossi S, Franze A, Marciano E, Capasso G, Simonelli F, Salvatore F. Genetic characterization of Italian patients with Bardet-Biedl syndrome and correlation to ocular, renal and audio-vestibular phenotype: identification of eleven novel pathogenic sequence variants. BMC Med Genet 2017;18:10.
52. Farkas MH, Lew DS, Sousa ME, Bujakowska K, Chatagnon J, Bhattacharya SS, Pierce EA, Nandrot EF. Mutations in pre-mRNA processing factors 3, 8, and 31 cause dysfunction of the retinal pigment epithelium. Am J Pathol 2014;184:2641-52.
53. Jerry Chiang WC, Lin JH. The effects of IRE1, ATF6, and PERK signaling on adRP-linked rhodopsins. Adv Exp Med Biol 2014;801:661-7.
54. Ruzickova S, Stanek D. Mutations in spliceosomal proteins and retina degeneration. RNA Biol 2017;14:544-552.
55. Yoshikawa T, Ogata N, Izuta H, Shimazawa M, Hara H, Takahashi K. Increased expression of tight junctions in ARPE-19 cells under endoplasmic reticulum stress. Curr Eye Res 2011;36:1153-63.
56. Schmidt-Kastner R, Kreczmanski P, Preising M, Diederen R, Schmitz C, Reis D, Blanks J, Dorey CK. Expression of the diabetes risk gene wolframin (WFS1) in the human retina. Exp Eye Res 2009;89:568-74.
57. Angius A, Uva P, Buers I, Oppo M, Puddu A, Onano S, Persico I, Loi A, Marcia L, Hohne W, Cuccuru G, Fotia G, Deiana M, Marongiu M, Atalay HT, Inan S, El Assy O, Smit LM, Okur I, Boduroglu K, Utine GE, Kilic E, Zampino G, Crisponi G, Crisponi L, Rutsch F. Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa. Am J Hum Genet 2016;99:236-45.
58. Wen Y, Locke KG, Klein M, Bowne SJ, Sullivan LS, Ray JW, Daiger SP, Birch DG, Hughbanks-Wheaton DK. Phenotypic characterization of 3 families with autosomal dominant retinitis pigmentosa due to mutations in KLHL7. Arch Ophthalmol 2011;129:1475-82.
59. Li L, Nakaya N, Chavali VR, Ma Z, Jiao X, Sieving PA, Riazuddin S, Tomarev SI, Ayyagari R, Riazuddin SA, Hejtmancik JF. A mutation in ZNF513, a putative regulator of photoreceptor development, causes autosomal-recessive retinitis pigmentosa. Am J Hum Genet 2010;87:400-9.
60. Tang K, Xie X, Park JI, Jamrich M, Tsai S, Tsai MJ. COUP-TFs regulate eye development by controlling factors essential for optic vesicle morphogenesis. Development 2010;137:725-34.
61. Cho KI, Yi H, Tserentsoodol N, Searle K, Ferreira PA. Neuroprotection resulting from insufficiency of RANBP2 is associated with the modulation of protein and lipid homeostasis of functionally diverse but linked pathways in response to oxidative stress. Dis Model Mech 2010;3:595-604.
62. Booij JC, Baas DC, Beisekeeva J, Gorgels TG, Bergen AA. The dynamic nature of Bruch’s membrane. Prog Retin Eye Res 2010;29:1-18.
63. Jomary C, Neal MJ, Jones SE. Increased expression of retinal TIMP3 mRNA in simplex retinitis pigmentosa is localized to photoreceptor-retaining regions. J Neurochem 1995;64:2370-3.
64. Fang M, Adams JS, McMahan BL, Brown RJ, Oxford JT. The expression patterns of minor fibrillar collagens during development in zebrafish. Gene Expr Patterns 2010;10:315-22.
65. Kirwan RP, Wordinger RJ, Clark AF, O’Brien CJ. Differential global and extra-cellular matrix focused gene expression patterns between normal and glaucomatous human lamina cribrosa cells. Mol Vis 2009;15:76-88.
66. Martin CA, Ahmad I, Klingseisen A, Hussain MS, Bicknell LS, Leitch A, Nurnberg G, Toliat MR, Murray JE, Hunt D, Khan F, Ali Z, Tinschert S, Ding J, Keith C, Harley ME, Heyn P, Muller R, Hoffmann I, Cormier-Daire V, Dollfus H, Dupuis L, Bashamboo A, McElreavey K, Kariminejad A, Mendoza-Londono R, Moore AT, Saggar A, Schlechter C, Weleber R, Thiele H, Altmuller J, Hohne W, Hurles ME, Noegel AA, Baig SM, Nurnberg P, Jackson AP. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat Genet 2014;46:1283-1292.
67. Choi SH, McCollum D. A role for metaphase spindle elongation forces in correction of merotelic kinetochore attachments. Curr Biol 2012;22:225-30.
68. Yao J, Jia L, Khan N, Lin C, Mitter SK, Boulton ME, Dunaief JL, Klionsky DJ, Guan JL, Thompson DA, Zacks DN. Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium. Autophagy 2015;11:939-53.
69. Yu S, Li C, Biswas L, Hu X, Liu F, Reilly J, Liu X, Liu Y, Huang Y, Lu Z, Han S, Wang L, Yu Liu J, Jiang T, Shu X, Wong F, Tang Z, Liu M. CERKL gene knockout disturbs photoreceptor outer segment phagocytosis and causes rod-cone dystrophy in zebrafish. Hum Mol Genet 2017;26:2335-2345.
70. Kevany BM, Palczewski K. Phagocytosis of retinal rod and cone photoreceptors. Physiology (Bethesda) 2010;25:8-15.
71. Xia H, Hu P, Yuan L, Xiong W, Xu H, Yi J, Yang Z, Deng X, Guo Y, Deng H. A homozygous MYO7A mutation associated to Usher syndrome and unilateral auditory neuropathy spectrum disorder. Mol Med Rep 2017;16:4241-4246.
72. Williams DS, Lopes VS. The many different cellular functions of MYO7A in the retina. Biochem Soc Trans 2011;39:1207-10.
73. Travis GH, Golczak M, Moise AR, Palczewski K. Diseases caused by defects in the visual cycle: retinoids as potential therapeutic agents. Annu Rev Pharmacol Toxicol 2007;47:469-512.
74. Parker RO, Crouch RK. Retinol dehydrogenases (RDHs) in the visual cycle. Exp Eye Res 2010;91:788-92.
75. Siemiatkowska AM, van den Born LI, van Hagen PM, Stoffels M, Neveling K, Henkes A, Kipping-Geertsema M, Hoefsloot LH, Hoyng CB, Simon A, den Hollander AI, Cremers FP, Collin RW. Mutations in the mevalonate kinase (MVK) gene cause nonsyndromic retinitis pigmentosa. Ophthalmology 2013;120:2697-705.
