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The Ubiquitin–Proteasome System in Retinal Health and Disease

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Abstract

The ubiquitin–proteasome system (UPS) is the main intracellular pathway for modulated protein turnover, playing an important role in the maintenance of cellular homeostasis. It also exerts a protein quality control through degradation of oxidized, mutant, denatured, or misfolded proteins and is involved in many biological processes where protein level regulation is necessary. This system allows the cell to modulate its protein expression pattern in response to changing physiological conditions and provides a critical protective role in health and disease. Impairments of UPS function in the central nervous system (CNS) underlie an increasing number of genetic and idiopathic diseases, many of which affect the retina. Current knowledge on the UPS composition and function in this tissue, however, is scarce and dispersed. This review focuses on UPS elements reported in the retina, including ubiquitinating and deubiquitinating enzymes (DUBs), and alternative proteasome assemblies. Known and inferred roles of protein ubiquitination, and of the related, SUMO conjugation (SUMOylation) process, in normal retinal development and adult homeostasis are addressed, including modulation of the visual cycle and response to retinal stress and injury. Additionally, the relationship between UPS dysfunction and human neurodegenerative disorders affecting the retina, including Alzheimer's, Parkinson's, and Huntington's diseases, are dealt with, together with numerous instances of retina-specific illnesses with UPS involvement, such as retinitis pigmentosa, macular degenerations, glaucoma, diabetic retinopathy (DR), and aging-related impairments. This information, though still basic and limited, constitutes a suitable framework to be expanded in incoming years and should prove orientative toward future therapy design targeting sight-affecting diseases with a UPS underlying basis.

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References

  1. Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479

    Article  PubMed  CAS  Google Scholar 

  2. Varshavsky A, Turner G, Du F, Xie Y (2000) The ubiquitin system and the N-end rule pathway. Biol Chem 381:779–789

    Article  PubMed  CAS  Google Scholar 

  3. Jahngen-Hodge J, Obin MS, Gong X, Shang F, Nowell TR Jr, Gong J, Abasi H, Blumberg J, Taylor A (1997) Regulation of ubiquitin-conjugating enzymes by glutathione following oxidative stress. J Biol Chem 272:28218–28226

    Article  PubMed  CAS  Google Scholar 

  4. Shang F, Gong X, Palmer HJ, Nowell TR Jr, Taylor A (1997) Age-related decline in ubiquitin conjugation in response to oxidative stress in the lens. Exp Eye Res 64:21–30

    Article  PubMed  CAS  Google Scholar 

  5. Jahngen JH, Haas AL, Ciechanover A, Blondin J, Eisenhauer D, Taylor A (1986) The eye lens has an active ubiquitin–protein conjugation system. J Biol Chem 261:13760–13767

    PubMed  CAS  Google Scholar 

  6. Fredrickson EK, Gardner RG (2012) Selective destruction of abnormal proteins by ubiquitin-mediated protein quality control degradation. Semin Cell Dev Biol 23:530–537

    Article  PubMed  CAS  Google Scholar 

  7. King RW, Deshaies RJ, Peters JM, Kirschner MW (1996) How proteolysis drives the cell cycle. Science 274:1652–1659

    Article  PubMed  CAS  Google Scholar 

  8. DeSalle LM, Pagano M (2001) Regulation of the G1 to S transition by the ubiquitin pathway. FEBS Lett 490:179–189

    Article  PubMed  CAS  Google Scholar 

  9. Yew PR (2001) Ubiquitin-mediated proteolysis of vertebrate G1- and S-phase regulators. J Cell Physiol 187:1–10

    Article  PubMed  CAS  Google Scholar 

  10. Clarke DJ (2002) Proteolysis and the cell cycle. Cell Cycle 1:233–234

    Article  PubMed  CAS  Google Scholar 

  11. Mocciaro A, Rape M (2012) Emerging regulatory mechanisms in ubiquitin-dependent cell cycle control. J Cell Sci 125:255–263

    Article  PubMed  CAS  Google Scholar 

  12. Peters JM (2002) The anaphase-promoting complex: proteolysis in mitosis and beyond. Mol Cell 9:931–943

    Article  PubMed  CAS  Google Scholar 

  13. Campbell DS, Holt CE (2001) Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 32:1013–1026

    Article  PubMed  CAS  Google Scholar 

  14. Geng F, Wenzel S, Tansey WP (2012) Ubiquitin and proteasomes in transcription. Annu Rev Biochem 81:177–201

    Article  PubMed  CAS  Google Scholar 

  15. Haglund K, Dikic I (2012) The role of ubiquitylation in receptor endocytosis and endosomal sorting. J Cell Sci 125:265–275

    Article  PubMed  CAS  Google Scholar 

  16. Thrower JS, Hoffman L, Rechsteiner M, Pickart CM (2000) Recognition of the polyubiquitin proteolytic signal. EMBO J 19:94–102

    Article  PubMed  CAS  Google Scholar 

  17. Chiu RK, Brun J, Ramaekers C, Theys J, Weng L, Lambin P, Gray DA, Wouters BG (2006) Lysine 63-polyubiquitination guards against translesion synthesis-induced mutations. PLoS Genet 2:e116

    Article  PubMed  CAS  Google Scholar 

  18. Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ (2000) Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103:351–361

    Article  PubMed  CAS  Google Scholar 

  19. Wickliffe KE, Williamson A, Meyer HJ, Kelly A, Rape M (2011) K11-linked ubiquitin chains as novel regulators of cell division. Trends Cell Biol 21:656–663

    Article  PubMed  CAS  Google Scholar 

  20. Pickart CM, Fushman D (2004) Polyubiquitin chains: polymeric protein signals. Curr Opin Chem Biol 8:610–616

    Article  PubMed  CAS  Google Scholar 

  21. Ye Y, Rape M (2009) Building ubiquitin chains: E2 enzymes at work. Nat Rev Mol Cell Biol 10:755–764

    Article  PubMed  CAS  Google Scholar 

  22. Melo SP, Barbour KW, Berger FG (2011) Cooperation between an intrinsically disordered region and a helical segment is required for ubiquitin-independent degradation by the proteasome. J Biol Chem 286:36559–36567

    Article  PubMed  CAS  Google Scholar 

  23. Ha SW, Ju D, Xie Y (2012) The N-terminal domain of Rpn4 serves as a portable ubiquitin-independent degron and is recognized by specific 19S RP subunits. Biochem Biophys Res Commun 419:226–231

    Article  PubMed  CAS  Google Scholar 

  24. Davies KJ (2001) Degradation of oxidized proteins by the 20S proteasome. Biochimie 83:301–310

    Article  PubMed  CAS  Google Scholar 

  25. Balog EM, Lockamy EL, Thomas DD, Ferrington DA (2009) Site-specific methionine oxidation initiates calmodulin degradation by the 20S proteasome. Biochemistry 48:3005–3016

    Article  PubMed  CAS  Google Scholar 

  26. Kisselev AF, Akopian TN, Woo KM, Goldberg AL (1999) The sizes of peptides generated from protein by mammalian 26 and 20 S proteasomes. Implications for understanding the degradative mechanism and antigen presentation. J Biol Chem 274:3363–3371

    Article  PubMed  CAS  Google Scholar 

  27. Glickman MH, Ciechanover A (2002) The ubiquitin–proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82:373–428

    PubMed  CAS  Google Scholar 

  28. Lehman NL (2009) The ubiquitin proteasome system in neuropathology. Acta Neuropathol 118:329–347

    Article  PubMed  CAS  Google Scholar 

  29. Ciechanover A, Brundin P (2003) The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40:427–446

    Article  PubMed  CAS  Google Scholar 

  30. Nandi D, Tahiliani P, Kumar A, Chandu D (2006) The ubiquitin–proteasome system. J Biosci 31:137–155

    Article  PubMed  CAS  Google Scholar 

  31. Noda C, Tanahashi N, Shimbara N, Hendil KB, Tanaka K (2000) Tissue distribution of constitutive proteasomes, immunoproteasomes, and PA28 in rats. Biochem Biophys Res Commun 277:348–354

    Article  PubMed  CAS  Google Scholar 

  32. Sixt SU, Alami R, Hakenbeck J, Adamzik M, Kloss A, Costabel U, Jungblut PR, Dahlmann B, Peters J (2012) Distinct proteasome subpopulations in the alveolar space of patients with the acute respiratory distress syndrome. Mediat Inflamm 2012:204250

    Article  CAS  Google Scholar 

  33. Bochtler M, Ditzel L, Groll M, Hartmann C, Huber R (1999) The proteasome. Annu Rev Biophys Biomol Struct 28:295–317

    Article  PubMed  CAS  Google Scholar 

  34. Groll M, Ditzel L, Lowe J, Stock D, Bochtler M, Bartunik HD, Huber R (1997) Structure of 20S proteasome from yeast at 2.4 Å resolution. Nature 386:463–471

    Article  PubMed  CAS  Google Scholar 

  35. Löwe J, Stock D, Jap B, Zwickl P, Baumeister W, Huber R (1995) Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 Å resolution. Science 268:533–539

    Article  PubMed  Google Scholar 

  36. Glickman MH, Rubin DM, Coux O, Wefes I, Pfeifer G, Cjeka Z, Baumeister W, Fried VA, Finley D (1998) A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3. Cell 94:615–623

    Article  PubMed  CAS  Google Scholar 

  37. Verma R, Chen S, Feldman R, Schieltz D, Yates J, Dohmen J, Deshaies RJ (2000) Proteasomal proteomics: identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity-purified proteasomes. Mol Biol Cell 11:3425–3439

    PubMed  CAS  Google Scholar 

  38. Lam YA, Xu W, DeMartino GN, Cohen RE (1997) Editing of ubiquitin conjugates by an isopeptidase in the 26S proteasome. Nature 385:737–740

    Article  PubMed  CAS  Google Scholar 

  39. Braun BC, Glickman M, Kraft R, Dahlmann B, Kloetzel PM, Finley D, Schmidt M (1999) The base of the proteasome regulatory particle exhibits chaperone-like activity. Nat Cell Biol 1:221–226

    Article  PubMed  CAS  Google Scholar 

  40. Horwich AL, Weber-Ban EU, Finley D (1999) Chaperone rings in protein folding and degradation. Proc Natl Acad Sci U S A 96:11033–11040

    Article  PubMed  CAS  Google Scholar 

  41. Kohler A, Cascio P, Leggett DS, Woo KM, Goldberg AL, Finley D (2001) The axial channel of the proteasome core particle is gated by the Rpt2 ATPase and controls both substrate entry and product release. Mol Cell 7:1143–1152

    Article  PubMed  CAS  Google Scholar 

  42. Strickland E, Hakala K, Thomas PJ, DeMartino GN (2000) Recognition of misfolding proteins by PA700, the regulatory subcomplex of the 26 S proteasome. J Biol Chem 275:5565–5572

    Article  PubMed  CAS  Google Scholar 

  43. Montel V, Gardrat F, Azanza JL, Raymond J (1999) 20S proteasome, hsp90, p97 fusion protein, PA28 activator copurifying oligomers and ATPase activities. Biochem Mol Biol Int 47:465–472

    PubMed  CAS  Google Scholar 

  44. Wagner BJ, Margolis JW (1995) Age-dependent association of isolated bovine lens multicatalytic proteinase complex (proteasome) with heat-shock protein 90, an endogenous inhibitor. Arch Biochem Biophys 323:455–462

    Article  PubMed  CAS  Google Scholar 

  45. Lee DH, Sherman MY, Goldberg AL (1996) Involvement of the molecular chaperone Ydj1 in the ubiquitin-dependent degradation of short-lived and abnormal proteins in Saccharomyces cerevisiae. Mol Cell Biol 16:4773–4781

    PubMed  CAS  Google Scholar 

  46. Marques C, Guo W, Pereira P, Taylor A, Patterson C, Evans PC, Shang F (2006) The triage of damaged proteins: degradation by the ubiquitin–proteasome pathway or repair by molecular chaperones. FASEB J 20:741–743

    PubMed  CAS  Google Scholar 

  47. Murata S, Minami Y, Minami M, Chiba T, Tanaka K (2001) CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep 2:1133–1138

    Article  PubMed  CAS  Google Scholar 

  48. Sumara I, Maerki S, Peter M (2008) E3 ubiquitin ligases and mitosis: embracing the complexity. Trends Cell Biol 18:84–94

    Article  PubMed  CAS  Google Scholar 

  49. Rondou P, Haegeman G, Vanhoenacker P, Van Craenenbroeck K (2008) BTB Protein KLHL12 targets the dopamine D4 receptor for ubiquitination by a Cul3-based E3 ligase. J Biol Chem 283:11083–11096

    Article  PubMed  CAS  Google Scholar 

  50. Surgucheva I, Ninkina N, Buchman VL, Grasing K, Surguchov A (2005) Protein aggregation in retinal cells and approaches to cell protection. Cell Mol Neurobiol 25:1051–1066

    Article  PubMed  Google Scholar 

  51. Hallermalm K, Seki K, Wei C, Castelli C, Rivoltini L, Kiessling R, Levitskaya J (2001) Tumor necrosis factor-α induces coordinated changes in major histocompatibility class I presentation pathway, resulting in increased stability of class I complexes at the cell surface. Blood 98:1108–1115

    Article  PubMed  CAS  Google Scholar 

  52. Kloetzel PM, Soza A, Stohwasser R (1999) The role of the proteasome system and the proteasome activator PA28 complex in the cellular immune response. Biol Chem 380:293–297

    Article  PubMed  CAS  Google Scholar 

  53. Nelson JE, Loukissa A, Altschuller-Felberg C, Monaco JJ, Fallon JT, Cardozo C (2000) Up-regulation of the proteasome subunit LMP7 in tissues of endotoxemic rats. J Lab Clin Med 135:324–331

    Article  PubMed  CAS  Google Scholar 

  54. Rock KL, Gramm C, Rothstein L, Clark K, Stein R, Dick L, Hwang D, Goldberg AL (1994) Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell 78:761–771

    Article  PubMed  CAS  Google Scholar 

  55. Goldberg AL, Cascio P, Saric T, Rock KL (2002) The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides. Mol Immunol 39:147–164

    Article  PubMed  CAS  Google Scholar 

  56. Louie JL, Kapphahn RJ, Ferrington DA (2002) Proteasome function and protein oxidation in the aged retina. Exp Eye Res 75:271–284

    PubMed  CAS  Google Scholar 

  57. Kapphahn RJ, Bigelow EJ, Ferrington DA (2007) Age-dependent inhibition of proteasome chymotrypsin-like activity in the retina. Exp Eye Res 84:646–654

    Article  PubMed  CAS  Google Scholar 

  58. Diaz-Hernandez M, Hernandez F, Martin-Aparicio E, Gomez-Ramos P, Moran MA, Castano JG, Ferrer I, Avila J, Lucas JJ (2003) Neuronal induction of the immunoproteasome in Huntington's disease. J Neurosci 23:11653–11661

    PubMed  CAS  Google Scholar 

  59. Mishto M, Bellavista E, Santoro A, Stolzing A, Ligorio C, Nacmias B, Spazzafumo L, Chiappelli M, Licastro F, Sorbi S, Pession A, Ohm T, Grune T, Franceschi C (2006) Immunoproteasome and LMP2 polymorphism in aged and Alzheimer's disease brains. Neurobiol Aging 27:54–66

    Article  PubMed  CAS  Google Scholar 

  60. Singh S, Awasthi N, Egwuagu CE, Wagner BJ (2002) Immunoproteasome expression in a nonimmune tissue, the ocular lens. Arch Biochem Biophys 405:147–153

    Article  PubMed  CAS  Google Scholar 

  61. Wilkinson KD, Tashayev VL, O'Connor LB, Larsen CN, Kasperek E, Pickart CM (1995) Metabolism of the polyubiquitin degradation signal: structure, mechanism, and role of isopeptidase T. Biochemistry 34:14535–14546

    Article  PubMed  CAS  Google Scholar 

  62. Mayer AN, Wilkinson KD (1989) Detection, resolution, and nomenclature of multiple ubiquitin carboxyl-terminal esterases from bovine calf thymus. Biochemistry 28:166–172

    Article  PubMed  CAS  Google Scholar 

  63. Wilkinson KD, Lee KM, Deshpande S, Duerksen-Hughes P, Boss JM, Pohl J (1989) The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase. Science 246:670–673

    Article  PubMed  CAS  Google Scholar 

  64. Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, Ishov AM, Tommerup N, Vissing H, Sekido Y, Minna J, Borodovsky A, Schultz DC, Wilkinson KD, Maul GG, Barlev N, Berger SL, Prendergast GC, Rauscher FJ 3rd (1998) BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16:1097–1112

    Article  PubMed  CAS  Google Scholar 

  65. Day IN, Thompson RJ (1987) Molecular cloning of cDNA coding for human PGP 9.5 protein. A novel cytoplasmic marker for neurones and neuroendocrine cells. FEBS Lett 210:157–160

    Article  PubMed  CAS  Google Scholar 

  66. Wilkinson KD, Deshpande S, Larsen CN (1992) Comparisons of neuronal (PGP 9.5) and non-neuronal ubiquitin C-terminal hydrolases. Biochem Soc Trans 20:631–637

    PubMed  CAS  Google Scholar 

  67. Kajimoto Y, Hashimoto T, Shirai Y, Nishino N, Kuno T, Tanaka C (1992) cDNA cloning and tissue distribution of a rat ubiquitin carboxyl-terminal hydrolase PGP9.5. J Biochem 112:28–32

    PubMed  CAS  Google Scholar 

  68. Lowe J, McDermott H, Landon M, Mayer RJ, Wilkinson KD (1990) Ubiquitin carboxyl-terminal hydrolase (PGP 9.5) is selectively present in ubiquitinated inclusion bodies characteristic of human neurodegenerative diseases. J Pathol 161:153–160

    Article  PubMed  CAS  Google Scholar 

  69. Day IN, Hinks LJ, Thompson RJ (1990) The structure of the human gene encoding protein gene product 9.5 (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase. Biochem J 268:521–524

    PubMed  CAS  Google Scholar 

  70. Hay RT (2001) Protein modification by SUMO. Trends Biochem Sci 26:332–333

    Article  PubMed  CAS  Google Scholar 

  71. Melchior F (2000) SUMO—nonclassical ubiquitin. Annu Rev Cell Dev Biol 16:591–626

    Article  PubMed  CAS  Google Scholar 

  72. Muller S, Hoege C, Pyrowolakis G, Jentsch S (2001) SUMO, ubiquitin's mysterious cousin. Nat Rev Mol Cell Biol 2:202–210

    Article  PubMed  CAS  Google Scholar 

  73. Johnson ES, Blobel G (1997) Ubc9p is the conjugating enzyme for the ubiquitin-like protein Smt3p. J Biol Chem 272:26799–26802

    Article  PubMed  CAS  Google Scholar 

  74. Desterro JM, Rodriguez MS, Kemp GD, Hay RT (1999) Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1. J Biol Chem 274:10618–10624

    Article  PubMed  CAS  Google Scholar 

  75. Desterro JM, Thomson J, Hay RT (1997) Ubch9 conjugates SUMO but not ubiquitin. FEBS Lett 417:297–300

    Article  PubMed  CAS  Google Scholar 

  76. Pichler A, Gast A, Seeler JS, Dejean A, Melchior F (2002) The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell 108:109–120

    Article  PubMed  CAS  Google Scholar 

  77. Johnson ES, Gupta AA (2001) An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell 106:735–744

    Article  PubMed  CAS  Google Scholar 

  78. Kahyo T, Nishida T, Yasuda H (2001) Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Mol Cell 8:713–718

    Article  PubMed  CAS  Google Scholar 

  79. Sachdev S, Bruhn L, Sieber H, Pichler A, Melchior F, Grosschedl R (2001) PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev 15:3088–3103

    Article  PubMed  CAS  Google Scholar 

  80. Takahashi Y, Kahyo T, Toh EA, Yasuda H, Kikuchi Y (2001) Yeast Ull1/Siz1 is a novel SUMO1/Smt3 ligase for septin components and functions as an adaptor between conjugating enzyme and substrates. J Biol Chem 276:48973–48977

    Article  PubMed  CAS  Google Scholar 

  81. Obin M, Nowell T, Taylor A (1994) The photoreceptor G-protein transducin (Gt) is a substrate for ubiquitin-dependent proteolysis. Biochem Biophys Res Commun 200:1169–1176

    Article  PubMed  CAS  Google Scholar 

  82. Obin M, Nowell T, Taylor A (1995) A comparison of ubiquitin-dependent proteolysis of rod outer segment proteins in reticulocyte lysate and a retinal pigment epithelial cell line. Curr Eye Res 14:751–760

    Article  PubMed  CAS  Google Scholar 

  83. Obin MS, Jahngen-Hodge J, Nowell T, Taylor A (1996) Ubiquitinylation and ubiquitin-dependent proteolysis in vertebrate photoreceptors (rod outer segments). Evidence for ubiquitinylation of Gt and rhodopsin. J Biol Chem 271:14473–14484

    Article  PubMed  CAS  Google Scholar 

  84. Naash MI, Al-Ubaidi MR, Anderson RE (1997) Light exposure induces ubiquitin conjugation and degradation activities in the rat retina. Investig Ophthalmol Vis Sci 38:2344–2354

    CAS  Google Scholar 

  85. Obin M, Lee BY, Meinke G, Bohm A, Lee RH, Gaudet R, Hopp JA, Arshavsky VY, Willardson BM, Taylor A (2002) Ubiquitylation of the transducin βγ subunit complex. Regulation by phosducin. J Biol Chem 277:44566–44575

    Article  PubMed  CAS  Google Scholar 

  86. Mirza S, Plafker KS, Aston C, Plafker SM (2010) Expression and distribution of the class III ubiquitin-conjugating enzymes in the retina. Mol Vis 16:2425–2437

    PubMed  CAS  Google Scholar 

  87. Kim JJ, Kim YH, Lee MY (2009) Proteomic characterization of differentially expressed proteins associated with no stress in retinal ganglion cells. BMB Rep 42:456–461

    Article  PubMed  CAS  Google Scholar 

  88. Drinjakovic J, Jung H, Campbell DS, Strochlic L, Dwivedy A, Holt CE (2010) E3 ligase Nedd4 promotes axon branching by downregulating PTEN. Neuron 65:341–357

    Article  PubMed  CAS  Google Scholar 

  89. Friedman JS, Ray JW, Waseem N, Johnson K, Brooks MJ, Hugosson T, Breuer D, Branham KE, Krauth DS, Bowne SJ, Sullivan LS, Ponjavic V, Granse L, Khanna R, Trager EH, Gieser LM, Hughbanks-Wheaton D, Cojocaru RI, Ghiasvand NM, Chakarova CF, Abrahamson M, Goring HH, Webster AR, Birch DG, Abecasis GR, Fann Y, Bhattacharya SS, Daiger SP, Heckenlively JR, Andreasson S, Swaroop A (2009) Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa. Am J Hum Genet 84:792–800

    Article  PubMed  CAS  Google Scholar 

  90. Chakarova CF, Papaioannou MG, Khanna H, Lopez I, Waseem N, Shah A, Theis T, Friedman J, Maubaret C, Bujakowska K, Veraitch B, Abd El-Aziz MM, De Prescott Q, Parapuram SK, Bickmore WA, Munro PM, Gal A, Hamel CP, Marigo V, Ponting CP, Wissinger B, Zrenner E, Matter K, Swaroop A, Koenekoop RK, Bhattacharya SS (2007) Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy. Am J Hum Genet 81:1098–1103

    Article  PubMed  CAS  Google Scholar 

  91. Rajendra R, Malegaonkar D, Pungaliya P, Marshall H, Rasheed Z, Brownell J, Liu LF, Lutzker S, Saleem A, Rubin EH (2004) Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. J Biol Chem 279:36440–36444

    Article  PubMed  CAS  Google Scholar 

  92. Kwon YT, Reiss Y, Fried VA, Hershko A, Yoon JK, Gonda DK, Sangan P, Copeland NG, Jenkins NA, Varshavsky A (1998) The mouse and human genes encoding the recognition component of the N-end rule pathway. Proc Natl Acad Sci U S A 95:7898–7903

    Article  PubMed  CAS  Google Scholar 

  93. Ozawa Y, Nakao K, Kurihara T, Shimazaki T, Shimmura S, Ishida S, Yoshimura A, Tsubota K, Okano H (2008) Roles of STAT3/SOCS3 pathway in regulating the visual function and ubiquitin–proteasome-dependent degradation of rhodopsin during retinal inflammation. J Biol Chem 283:24561–24570

    Article  PubMed  CAS  Google Scholar 

  94. Balastik M, Ferraguti F, Pires-da Silva A, Lee TH, Alvarez-Bolado G, Lu KP, Gruss P (2008) Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration. Proc Natl Acad Sci U S A 105:12016–12021

    Article  PubMed  CAS  Google Scholar 

  95. Yego EC, Mohr S (2010) siah-1 Protein is necessary for high glucose-induced glyceraldehyde-3-phosphate dehydrogenase nuclear accumulation and cell death in Müller cells. J Biol Chem 285:3181–3190

    Article  PubMed  CAS  Google Scholar 

  96. Dev KK, Van der Putten H, Sommer B, Rovelli G (2003) Part I: parkin-associated proteins and Parkinson's disease. Neuropharmacology 45:1–13

    Article  PubMed  CAS  Google Scholar 

  97. Tan JM, Wong ES, Lim KL (2009) Protein misfolding and aggregation in Parkinson's disease. Antioxid Redox Signal 11:2119–2134

    Article  PubMed  CAS  Google Scholar 

  98. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25:302–305

    Article  PubMed  CAS  Google Scholar 

  99. Esteve-Rudd J, Campello L, Herrero MT, Cuenca N, Martín-Nieto J (2010) Expression in the mammalian retina of parkin and UCH-L1, two components of the ubiquitin–proteasome system. Brain Res 1352:70–82

    Article  PubMed  CAS  Google Scholar 

  100. Bizzi A, Schaetzle B, Patton A, Gambetti P, Autilio-Gambetti L (1991) Axonal transport of two major components of the ubiquitin system: free ubiquitin and ubiquitin carboxyl-terminal hydrolase PGP 9.5. Brain Res 548:292–299

    Article  PubMed  CAS  Google Scholar 

  101. Chen ST, Von Bussmann KA, Garey LJ, Jen LS (1994) Protein gene product 9.5-immunoreactive retinal neurons in normal developing rats and rats with optic nerve or tract lesion. Brain Res Dev Brain Res 78:265–272

    Article  PubMed  CAS  Google Scholar 

  102. Piccinini M, Merighi A, Bruno R, Cascio P, Curto M, Mioletti S, Ceruti C, Rinaudo MT (1996) Affinity purification and characterization of protein gene product 9.5 (PGP9.5) from retina. Biochem J 318:711–716

    PubMed  CAS  Google Scholar 

  103. Bonfanti L, Candeo P, Piccinini M, Carmignoto G, Comelli MC, Ghidella S, Bruno R, Gobetto A, Merighi A (1992) Distribution of protein gene product 9.5 (PGP 9.5) in the vertebrate retina: evidence that immunoreactivity is restricted to mammalian horizontal and ganglion cells. J Comp Neurol 322:35–44

    Article  PubMed  CAS  Google Scholar 

  104. Loeffler KU, Mangini NJ (1997) Immunolocalization of ubiquitin and related enzymes in human retina and retinal pigment epithelium. Graefes Arch Clin Exp Ophthalmol 235:248–254

    Article  PubMed  CAS  Google Scholar 

  105. Glenn JV, Mahaffy H, Dasari S, Oliver M, Chen M, Boulton ME, Xu H, Curry WJ, Stitt AW (2012) Proteomic profiling of human retinal pigment epithelium exposed to an advanced glycation-modified substrate. Graefes Arch Clin Exp Ophthalmol 250:349–359

    Article  PubMed  CAS  Google Scholar 

  106. Sano Y, Furuta A, Setsuie R, Kikuchi H, Wang YL, Sakurai M, Kwon J, Noda M, Wada K (2006) Photoreceptor cell apoptosis in the retinal degeneration of Uchl3-deficient mice. Am J Pathol 169:132–141

    Article  PubMed  CAS  Google Scholar 

  107. Hansen-Hagge TE, Janssen JW, Hameister H, Papa FR, Zechner U, Seriu T, Jauch A, Becke D, Hochstrasser M, Bartram CR (1998) An evolutionarily conserved gene on human chromosome 5q33-q34, UBH1, encodes a novel deubiquitinating enzyme. Genomics 49:411–418

    Article  PubMed  CAS  Google Scholar 

  108. Swanson DA, Freund CL, Ploder L, McInnes RR, Valle D (1996) A ubiquitin C-terminal hydrolase gene on the proximal short arm of the X chromosome: implications for X-linked retinal disorders. Hum Mol Genet 5:533–538

    Article  PubMed  CAS  Google Scholar 

  109. Fischer-Vize JA, Rubin GM, Lehmann R (1992) The fat facets gene is required for Drosophila eye and embryo development. Development 116:985–1000

    PubMed  CAS  Google Scholar 

  110. Ethen CM, Hussong SA, Reilly C, Feng X, Olsen TW, Ferrington DA (2007) Transformation of the proteasome with age-related macular degeneration. FEBS Lett 581:885–890

    Article  PubMed  CAS  Google Scholar 

  111. Ferrington DA, Hussong SA, Roehrich H, Kapphahn RJ, Kavanaugh SM, Heuss ND, Gregerson DS (2008) Immunoproteasome responds to injury in the retina and brain. J Neurochem 106:158–169

    Article  PubMed  CAS  Google Scholar 

  112. Ferreira PA, Hom JT, Pak WL (1995) Retina-specifically expressed novel subtypes of bovine cyclophilin. J Biol Chem 270:23179–23188

    Article  PubMed  CAS  Google Scholar 

  113. Ferreira PA, Yunfei C, Schick D, Roepman R (1998) The cyclophilin-like domain mediates the association of Ran-binding protein 2 with subunits of the 19 S regulatory complex of the proteasome. J Biol Chem 273:24676–24682

    Article  PubMed  CAS  Google Scholar 

  114. Ferreira PA, Nakayama TA, Travis GH (1997) Interconversion of red opsin isoforms by the cyclophilin-related chaperone protein Ran-binding protein 2. Proc Natl Acad Sci U S A 94:1556–1561

    Article  PubMed  CAS  Google Scholar 

  115. Onishi A, Peng GH, Hsu C, Alexis U, Chen S, Blackshaw S (2009) Pias3-dependent SUMOylation directs rod photoreceptor development. Neuron 61:234–246

    Article  PubMed  CAS  Google Scholar 

  116. Grimm LM, Goldberg AL, Poirier GG, Schwartz LM, Osborne BA (1996) Proteasomes play an essential role in thymocyte apoptosis. EMBO J 15:3835–3844

    PubMed  CAS  Google Scholar 

  117. Cui H, Matsui K, Omura S, Schauer SL, Matulka RA, Sonenshein GE, Ju ST (1997) Proteasome regulation of activation-induced T cell death. Proc Natl Acad Sci U S A 94:7515–7520

    Article  PubMed  CAS  Google Scholar 

  118. Linden R, Rehen SK, Chiarini LB (1999) Apoptosis in developing retinal tissue. Prog Retin Eye Res 18:133–165

    Article  PubMed  CAS  Google Scholar 

  119. Neves DD, Rehen SK, Linden R (2001) Differentiation-dependent sensitivity to cell death induced in the developing retina by inhibitors of the ubiquitin–proteasome proteolytic pathway. Eur J Neurosci 13:1938–1944

    Article  PubMed  CAS  Google Scholar 

  120. Avci HX, Zelina P, Thelen K, Pollerberg GE (2004) Role of cell adhesion molecule DM-GRASP in growth and orientation of retinal ganglion cell axons. Dev Biol 271:291–305

    Article  PubMed  CAS  Google Scholar 

  121. Thelen K, Georg T, Bertuch S, Zelina P, Pollerberg GE (2008) Ubiquitination and endocytosis of cell adhesion molecule DM-GRASP regulate its cell surface presence and affect its role for axon navigation. J Biol Chem 283:32792–32801

    Article  PubMed  CAS  Google Scholar 

  122. Strissel KJ, Sokolov M, Trieu LH, Arshavsky VY (2006) Arrestin translocation is induced at a critical threshold of visual signaling and is superstoichiometric to bleached rhodopsin. J Neurosci 26:1146–1153

    Article  PubMed  CAS  Google Scholar 

  123. Song X, Raman D, Gurevich EV, Vishnivetskiy SA, Gurevich VV (2006) Visual and both non-visual arrestins in their “inactive” conformation bind JNK3 and Mdm2 and relocalize them from the nucleus to the cytoplasm. J Biol Chem 281:21491–21499

    Article  PubMed  CAS  Google Scholar 

  124. Bhattacharya S, Ray RM, Chaum E, Johnson DA, Johnson LR (2011) Inhibition of Mdm2 sensitizes human retinal pigment epithelial cells to apoptosis. Investig Ophthalmol Vis Sci 52:3368–3380

    Article  CAS  Google Scholar 

  125. Von Schantz M, Szel A, Van Veen T, Farber DB (1994) Expression of phototransduction cascade genes in the ground squirrel retina. Investig Ophthalmol Vis Sci 35:2558–2566

    Google Scholar 

  126. Bauer PH, Muller S, Puzicha M, Pippig S, Obermaier B, Helmreich EJ, Lohse MJ (1992) Phosducin is a protein kinase A-regulated G-protein regulator. Nature 358:73–76

    Article  PubMed  CAS  Google Scholar 

  127. Yoshida T, Willardson BM, Wilkins JF, Jensen GJ, Thornton BD, Bitensky MW (1994) The phosphorylation state of phosducin determines its ability to block transducin subunit interactions and inhibit transducin binding to activated rhodopsin. J Biol Chem 269:24050–24057

    PubMed  CAS  Google Scholar 

  128. Willardson BM, Wilkins JF, Yoshida T, Bitensky MW (1996) Regulation of phosducin phosphorylation in retinal rods by Ca2+/calmodulin-dependent adenylyl cyclase. Proc Natl Acad Sci U S A 93:1475–1479

    Article  PubMed  CAS  Google Scholar 

  129. Zhu X, Craft CM (1998) Interaction of phosducin and phosducin isoforms with a 26S proteasomal subunit, SUG1. Mol Vis 4:13

    PubMed  CAS  Google Scholar 

  130. Barhite S, Thibault C, Miles MF (1998) Phosducin-like protein (PhLP), a regulator of Gβγ function, interacts with the proteasomal protein SUG1. Biochim Biophys Acta 1402:95–101

    Article  PubMed  CAS  Google Scholar 

  131. Klenk C, Humrich J, Quitterer U, Lohse MJ (2006) SUMO-1 controls the protein stability and the biological function of phosducin. J Biol Chem 281:8357–8364

    Article  PubMed  CAS  Google Scholar 

  132. Ferreira PA, Nakayama TA, Pak WL, Travis GH (1996) Cyclophilin-related protein RanBP2 acts as chaperone for red/green opsin. Nature 383:637–640

    Article  PubMed  CAS  Google Scholar 

  133. Young RW (1976) Visual cells and the concept of renewal. Investig Ophthalmol Vis Sci 15:700–725

    CAS  Google Scholar 

  134. Schremser JL, Williams TP (1995) Rod outer segment (ROS) renewal as a mechanism for adaptation to a new intensity environment. I. Rhodopsin levels and ROS length. Exp Eye Res 61:17–23

    Article  PubMed  CAS  Google Scholar 

  135. Schremser JL, Williams TP (1995) Rod outer segment (ROS) renewal as a mechanism for adaptation to a new intensity environment. II. Rhodopsin synthesis and packing density. Exp Eye Res 61:25–32

    Article  PubMed  CAS  Google Scholar 

  136. Reme C (1981) Autophagy in rods and cones of the vertebrate retina. Dev Ophthalmol 4:101–148

    Article  PubMed  CAS  Google Scholar 

  137. Reme CE, Wolfrum U, Imsand C, Hafezi F, Williams TP (1999) Photoreceptor autophagy: effects of light history on number and opsin content of degradative vacuoles. Investig Ophthalmol Vis Sci 40:2398–2404

    CAS  Google Scholar 

  138. Hicke L, Riezman H (1996) Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis. Cell 84:277–287

    Article  PubMed  CAS  Google Scholar 

  139. Green CB, Besharse JC (2004) Retinal circadian clocks and control of retinal physiology. J Biol Rhythm 19:91–102

    Article  CAS  Google Scholar 

  140. Iuvone PM, Tosini G, Pozdeyev N, Haque R, Klein DC, Chaurasia SS (2005) Circadian clocks, clock networks, arylalkylamine N-acetyltransferase, and melatonin in the retina. Prog Retin Eye Res 24:433–456

    Article  PubMed  CAS  Google Scholar 

  141. Pozdeyev N, Taylor C, Haque R, Chaurasia SS, Visser A, Thazyeen A, Du Y, Fu H, Weller J, Klein DC, Iuvone PM (2006) Photic regulation of arylalkylamine N-acetyltransferase binding to 14-3-3 proteins in retinal photoreceptor cells. J Neurosci 26:9153–9161

    Article  PubMed  CAS  Google Scholar 

  142. Hussong SA, Roehrich H, Kapphahn RJ, Maldonado M, Pardue MT, Ferrington DA (2011) A novel role for the immunoproteasome in retinal function. Investig Ophthalmol Vis Sci 52:714–723

    Article  CAS  Google Scholar 

  143. Shang F, Taylor A (1995) Oxidative stress and recovery from oxidative stress are associated with altered ubiquitin conjugating and proteolytic activities in bovine lens epithelial cells. Biochem J 307:297–303

    PubMed  CAS  Google Scholar 

  144. Obin M, Shang F, Gong X, Handelman G, Blumberg J, Taylor A (1998) Redox regulation of ubiquitin-conjugating enzymes: mechanistic insights using the thiol-specific oxidant diamide. FASEB J 12:561–569

    PubMed  CAS  Google Scholar 

  145. Shang F, Gong X, Taylor A (1997) Activity of ubiquitin-dependent pathway in response to oxidative stress. Ubiquitin-activating enzyme is transiently up-regulated. J Biol Chem 272:23086–23093

    Article  PubMed  CAS  Google Scholar 

  146. Yao D, Gu Z, Nakamura T, Shi ZQ, Ma Y, Gaston B, Palmer LA, Rockenstein EM, Zhang Z, Masliah E, Uehara T, Lipton SA (2004) Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proc Natl Acad Sci U S A 101:10810–10814

    Article  PubMed  CAS  Google Scholar 

  147. Siu AW, Lau MK, Cheng JS, Chow CK, Tam WC, Li KK, Lee DK, To TS, To CH, Do CW (2008) Glutamate-induced retinal lipid and protein damage: the protective effects of catechin. Neurosci Lett 432:193–197

    Article  PubMed  CAS  Google Scholar 

  148. Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13

    Article  PubMed  CAS  Google Scholar 

  149. Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, Klose J, Shen J (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 279:18614–18622

    Article  PubMed  CAS  Google Scholar 

  150. Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803

    Article  PubMed  CAS  Google Scholar 

  151. Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou YS, Saiki S, Kawajiri S, Sato F, Kimura M, Komatsu M, Hattori N, Tanaka K (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189:211–221

    Article  PubMed  CAS  Google Scholar 

  152. Hara MR, Agrawal N, Kim SF, Cascio MB, Fujimuro M, Ozeki Y, Takahashi M, Cheah JH, Tankou SK, Hester LD, Ferris CD, Hayward SD, Snyder SH, Sawa A (2005) S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol 7:665–674

    Article  PubMed  CAS  Google Scholar 

  153. Hara MR, Cascio MB, Sawa A (2006) GAPDH as a sensor of NO stress. Biochim Biophys Acta 1762:502–509

    Article  PubMed  CAS  Google Scholar 

  154. Hara MR, Snyder SH (2006) Nitric oxide–GAPDH–Siah: a novel cell death cascade. Cell Mol Neurobiol 26:527–538

    Article  PubMed  CAS  Google Scholar 

  155. Barbini L, Rodriguez J, Dominguez F, Vega F (2007) Glyceraldehyde-3-phosphate dehydrogenase exerts different biologic activities in apoptotic and proliferating hepatocytes according to its subcellular localization. Mol Cell Biochem 300:19–28

    Article  PubMed  CAS  Google Scholar 

  156. Souza JM, Choi I, Chen Q, Weisse M, Daikhin E, Yudkoff M, Obin M, Ara J, Horwitz J, Ischiropoulos H (2000) Proteolytic degradation of tyrosine nitrated proteins. Arch Biochem Biophys 380:360–366

    Article  PubMed  CAS  Google Scholar 

  157. Petrs-Silva H, De Freitas FG, Linden R, Chiarini LB (2004) Early nuclear exclusion of the transcription factor max is associated with retinal ganglion cell death independent of caspase activity. J Cell Physiol 198:179–187

    Article  PubMed  CAS  Google Scholar 

  158. Petrs-Silva H, Chiarini LB, Linden R (2008) Nuclear proteasomal degradation and cytoplasmic retention underlie early nuclear exclusion of transcription factor Max upon axon damage. Exp Neurol 213:202–209

    Article  PubMed  CAS  Google Scholar 

  159. Xu W, Gong L, Haddad MM, Bischof O, Campisi J, Yeh ET, Medrano EE (2000) Regulation of microphthalmia-associated transcription factor MITF protein levels by association with the ubiquitin-conjugating enzyme hUBC9. Exp Cell Res 255:135–143

    Article  PubMed  CAS  Google Scholar 

  160. Galy A, Néron B, Planque N, Saule S, Eychène A (2002) Activated MAPK/ERK kinase (MEK-1) induces transdifferentiation of pigmented epithelium into neural retina. Dev Biol 248:251–264

    Article  PubMed  CAS  Google Scholar 

  161. Fernandes AF, Guo W, Zhang X, Gallagher M, Ivan M, Taylor A, Pereira P, Shang F (2006) Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells. Exp Eye Res 83:1472–1481

    Article  PubMed  CAS  Google Scholar 

  162. Kaarniranta K, Salminen A, Eskelinen EL, Kopitz J (2009) Heat shock proteins as gatekeepers of proteolytic pathways—implications for age-related macular degeneration (AMD). Ageing Res Rev 8:128–139

    Article  PubMed  CAS  Google Scholar 

  163. Kopito RR (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10:524–530

    Article  PubMed  CAS  Google Scholar 

  164. Wojcik C (2002) Regulation of apoptosis by the ubiquitin and proteasome pathway. J Cell Mol Med 6:25–48

    Article  PubMed  CAS  Google Scholar 

  165. Iwata A, Riley BE, Johnston JA, Kopito RR (2005) HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J Biol Chem 280:40282–40292

    Article  PubMed  CAS  Google Scholar 

  166. Pandey UB, Batlevi Y, Baehrecke EH, Taylor JP (2007) HDAC6 at the intersection of autophagy, the ubiquitin–proteasome system and neurodegeneration. Autophagy 3:643–645

    PubMed  CAS  Google Scholar 

  167. Zhang X, Zhou J, Fernandes AF, Sparrow JR, Pereira P, Taylor A, Shang F (2008) The proteasome: a target of oxidative damage in cultured human retina pigment epithelial cells. Investig Ophthalmol Vis Sci 49:3622–3630

    Article  Google Scholar 

  168. Fernandes AF, Zhou J, Zhang X, Bian Q, Sparrow J, Taylor A, Pereira P, Shang F (2008) Oxidative inactivation of the proteasome in retinal pigment epithelial cells. A potential link between oxidative stress and up-regulation of interleukin-8. J Biol Chem 283:20745–20753

    Article  PubMed  CAS  Google Scholar 

  169. Fernandes AF, Bian Q, Jiang JK, Thomas CJ, Taylor A, Pereira P, Shang F (2009) Proteasome inactivation promotes p38 mitogen-activated protein kinase-dependent phosphatidylinositol 3-kinase activation and increases interleukin-8 production in retinal pigment epithelial cells. Mol Biol Cell 20:3690–3699

    Article  PubMed  CAS  Google Scholar 

  170. Blanks JC, Hinton DR, Sadun AA, Miller CA (1989) Retinal ganglion cell degeneration in Alzheimer's disease. Brain Res 501:364–372

    Article  PubMed  CAS  Google Scholar 

  171. Gregory MH, Rutty DA, Wood RD (1970) Differences in the retinotoxic action of chloroquine and phenothiazine derivatives. J Pathol 102:139–150

    Article  PubMed  CAS  Google Scholar 

  172. Yoshida T, Fukatsu R, Tsuzuki K, Aizawa Y, Hayashi Y, Sasaki N, Takamaru Y, Fujii N, Takahata N (1997) Amyloid precursor protein, Aβ and amyloid-associated proteins involved in chloroquine retinopathy in rats—immunopathological studies. Brain Res 764:283–288

    Article  PubMed  CAS  Google Scholar 

  173. Cuenca N, Herrero MT, Angulo A, De Juan E, Martínez-Navarrete GC, López S, Barcia C, Martín-Nieto J (2005) Morphological impairments in retinal neurons of the scotopic visual pathway in a monkey model of Parkinson's disease. J Comp Neurol 493:261–273

    Article  PubMed  CAS  Google Scholar 

  174. Archibald NK, Clarke MP, Mosimann UP, Burn DJ (2009) The retina in Parkinson's disease. Brain 132:1128–1145

    Article  PubMed  Google Scholar 

  175. Bodis-Wollner I (2009) Retinopathy in Parkinson disease. J Neural Transm 116:1493–1501

    Article  PubMed  Google Scholar 

  176. Dauer W, Przedborski S (2003) Parkinson's disease: mechanisms and models. Neuron 39:889–909

    Article  PubMed  CAS  Google Scholar 

  177. Martínez-Navarrete GC, Martín-Nieto J, Esteve-Rudd J, Angulo A, Cuenca N (2007) α-Synuclein gene expression profile in the retina of vertebrates. Mol Vis 13:949–961

    PubMed  Google Scholar 

  178. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608

    Article  PubMed  CAS  Google Scholar 

  179. Engelender S (2012) α-Synuclein fate: proteasome or autophagy? Autophagy 8:418–420

    Article  PubMed  CAS  Google Scholar 

  180. Tobin AJ, Signer ER (2000) Huntington's disease: the challenge for cell biologists. Trends Cell Biol 10:531–536

    Article  PubMed  CAS  Google Scholar 

  181. Paulus W, Schwarz G, Werner A, Lange H, Bayer A, Hofschuster M, Muller N, Zrenner E (1993) Impairment of retinal increment thresholds in Huntington's disease. Ann Neurol 34:574–578

    Article  PubMed  CAS  Google Scholar 

  182. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506

    Article  PubMed  CAS  Google Scholar 

  183. Petrasch-Parwez E, Habbes HW, Weickert S, Lobbecke-Schumacher M, Striedinger K, Wieczorek S, Dermietzel R, Epplen JT (2004) Fine-structural analysis and connexin expression in the retina of a transgenic model of Huntington's disease. J Comp Neurol 479:181–197

    Article  PubMed  CAS  Google Scholar 

  184. Meade CA, Deng YP, Fusco FR, Del Mar N, Hersch S, Goldowitz D, Reiner A (2002) Cellular localization and development of neuronal intranuclear inclusions in striatal and cortical neurons in R6/2 transgenic mice. J Comp Neurol 449:241–269

    Article  PubMed  Google Scholar 

  185. Sroka K, Voigt A, Deeg S, Reed JC, Schulz JB, Bahr M, Kermer P (2009) BAG1 modulates huntingtin toxicity, aggregation, degradation, and subcellular distribution. J Neurochem 111:801–807

    Article  PubMed  CAS  Google Scholar 

  186. Martin JJ, Van Regemorter N, Krols L, Brucher JM, De Barsy T, Szliwowski H, Evrard P, Ceuterick C, Tassignon MJ, Smet-Dieleman H, Hayez-Delatte F, Willems PJ, Van Broeckhoven C (1994) On an autosomal dominant form of retinal–cerebellar degeneration: an autopsy study of five patients in one family. Acta Neuropathol 88:277–286

    Article  PubMed  CAS  Google Scholar 

  187. Yvert G, Lindenberg KS, Picaud S, Landwehrmeyer GB, Sahel JA, Mandel JL (2000) Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice. Hum Mol Genet 9:2491–2506

    Article  PubMed  CAS  Google Scholar 

  188. Mauger C, Del-Favero J, Ceuterick C, Lubke U, Van Broeckhoven C, Martin J (1999) Identification and localization of ataxin-7 in brain and retina of a patient with cerebellar ataxia type II using anti-peptide antibody. Brain Res Mol Brain Res 74:35–43

    Article  PubMed  CAS  Google Scholar 

  189. Holmberg M, Duyckaerts C, Durr A, Cancel G, Gourfinkel-An I, Damier P, Faucheux B, Trottier Y, Hirsch EC, Agid Y, Brice A (1998) Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet 7:913–918

    Article  PubMed  CAS  Google Scholar 

  190. Cummings CJ, Reinstein E, Sun Y, Antalffy B, Jiang Y, Ciechanover A, Orr HT, Beaudet AL, Zoghbi HY (1999) Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24:879–892

    Article  PubMed  CAS  Google Scholar 

  191. Wyttenbach A, Carmichael J, Swartz J, Furlong RA, Narain Y, Rankin J, Rubinsztein DC (2000) Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease. Proc Natl Acad Sci U S A 97:2898–2903

    Article  PubMed  CAS  Google Scholar 

  192. De Cristofaro T, Affaitati A, Cariello L, Avvedimento EV, Varrone S (1999) The length of polyglutamine tract, its level of expression, the rate of degradation, and the transglutaminase activity influence the formation of intracellular aggregates. Biochem Biophys Res Commun 260:150–158

    Article  PubMed  Google Scholar 

  193. Hugosson T, Friedman JS, Ponjavic V, Abrahamson M, Swaroop A, Andreasson S (2010) Phenotype associated with mutation in the recently identified autosomal dominant retinitis pigmentosa KLHL7 gene. Arch Ophthalmol 128:772–778

    Article  PubMed  CAS  Google Scholar 

  194. Kigoshi Y, Tsuruta F, Chiba T (2011) Ubiquitin ligase activity of Cul3–KLHL7 protein is attenuated by autosomal dominant retinitis pigmentosa causative mutation. J Biol Chem 286:33613–33621

    Article  PubMed  CAS  Google Scholar 

  195. Illing ME, Rajan RS, Bence NF, Kopito RR (2002) A rhodopsin mutant linked to autosomal dominant retinitis pigmentosa is prone to aggregate and interacts with the ubiquitin proteasome system. J Biol Chem 277:34150–34160

    Article  PubMed  CAS  Google Scholar 

  196. Saliba RS, Munro PM, Luthert PJ, Cheetham ME (2002) The cellular fate of mutant rhodopsin: quality control, degradation and aggresome formation. J Cell Sci 115:2907–2918

    PubMed  CAS  Google Scholar 

  197. Vasireddy V, Jablonski MM, Khan NW, Wang XF, Sahu P, Sparrow JR, Ayyagari R (2009) Elovl4 5-bp deletion knock-in mouse model for Stargardt-like macular degeneration demonstrates accumulation of ELOVL4 and lipofuscin. Exp Eye Res 89:905–912

    Article  PubMed  CAS  Google Scholar 

  198. Beatty S, Koh H, Phil M, Henson D, Boulton M (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 45:115–134

    Article  PubMed  CAS  Google Scholar 

  199. Holz FG, Pauleikhoff D, Klein R, Bird AC (2004) Pathogenesis of lesions in late age-related macular disease. Am J Ophthalmol 137:504–510

    Article  PubMed  Google Scholar 

  200. Nowak JZ (2006) Age-related macular degeneration (AMD): pathogenesis and therapy. Pharmacol Rep 58:353–363

    PubMed  CAS  Google Scholar 

  201. Boulton M, Roanowska M, Wess T (2004) Ageing of the retinal pigment epithelium: implications for transplantation. Graefes Arch Clin Exp Ophthalmol 242:76–84

    Article  PubMed  Google Scholar 

  202. Zarbin MA (2004) Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 122:598–614

    Article  PubMed  Google Scholar 

  203. Zhou J, Cai B, Jang YP, Pachydaki S, Schmidt AM, Sparrow JR (2005) Mechanisms for the induction of HNE- MDA- and AGE-adducts, RAGE and VEGF in retinal pigment epithelial cells. Exp Eye Res 80:567–580

    Article  PubMed  CAS  Google Scholar 

  204. Hjelmeland LM, Cristofolo VJ, Funk W, Rakoczy E, Katz ML (1999) Senescence of the retinal pigment epithelium. Mol Vis 5:33

    PubMed  CAS  Google Scholar 

  205. Winkler BS, Boulton ME, Gottsch JD, Sternberg P (1999) Oxidative damage and age-related macular degeneration. Mol Vis 5:32

    PubMed  CAS  Google Scholar 

  206. Decanini A, Nordgaard CL, Feng X, Ferrington DA, Olsen TW (2007) Changes in select redox proteins of the retinal pigment epithelium in age-related macular degeneration. Am J Ophthalmol 143:607–615

    Article  PubMed  CAS  Google Scholar 

  207. Pirkkala L, Alastalo TP, Zuo X, Benjamin IJ, Sistonen L (2000) Disruption of heat shock factor 1 reveals an essential role in the ubiquitin proteolytic pathway. Mol Cell Biol 20:2670–2675

    Article  PubMed  CAS  Google Scholar 

  208. Kaarniranta K, Ryhanen T, Karjalainen HM, Lammi MJ, Suuronen T, Huhtala A, Kontkanen M, Terasvirta M, Uusitalo H, Salminen A (2005) Geldanamycin increases 4-hydroxynonenal (HNE)-induced cell death in human retinal pigment epithelial cells. Neurosci Lett 382:185–190

    Article  PubMed  CAS  Google Scholar 

  209. Ryhanen T, Mannermaa E, Oksala N, Viiri J, Paimela T, Salminen A, Atalay M, Kaarniranta K (2008) Radicicol but not geldanamycin evokes oxidative stress response and efflux protein inhibition in ARPE-19 human retinal pigment epithelial cells. Eur J Pharmacol 584:229–236

    Article  PubMed  CAS  Google Scholar 

  210. McGeer EG, Klegeris A, McGeer PL (2005) Inflammation, the complement system and the diseases of aging. Neurobiol Aging 26(Suppl 1):94–97

    Article  PubMed  CAS  Google Scholar 

  211. Donoso LA, Kim D, Frost A, Callahan A, Hageman G (2006) The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 51:137–152

    Article  PubMed  Google Scholar 

  212. Zhou J, Jang YP, Kim SR, Sparrow JR (2006) Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium. Proc Natl Acad Sci U S A 103:16182–16187

    Article  PubMed  CAS  Google Scholar 

  213. Teoh CY, Davies KJ (2004) Potential roles of protein oxidation and the immunoproteasome in MHC class I antigen presentation: the ‘PrOxI’ hypothesis. Arch Biochem Biophys 423:88–96

    Article  PubMed  CAS  Google Scholar 

  214. Ding Q, Martin S, Dimayuga E, Bruce-Keller AJ, Keller JN (2006) LMP2 knock-out mice have reduced proteasome activities and increased levels of oxidatively damaged proteins. Antioxid Redox Signal 8:130–135

    Article  PubMed  CAS  Google Scholar 

  215. Kotamraju S, Matalon S, Matsunaga T, Shang T, Hickman-Davis JM, Kalyanaraman B (2006) Upregulation of immunoproteasomes by nitric oxide: potential antioxidative mechanism in endothelial cells. Free Radic Biol Med 40:1034–1044

    Article  PubMed  CAS  Google Scholar 

  216. De Gregorio F, Pecori-Giraldi J, De Stefano C, Virno M (1997) Correlation between ocular hypertension induced by ibopamine and perimetric defect in primary open-angle glaucoma. Eur J Ophthalmol 7:152–155

    PubMed  Google Scholar 

  217. Friedman DS, Wilson MR, Liebmann JM, Fechtner RD, Weinreb RN (2004) An evidence-based assessment of risk factors for the progression of ocular hypertension and glaucoma. Am J Ophthalmol 138:S19–S31

    Article  PubMed  Google Scholar 

  218. Quigley HA, Enger C, Katz J, Sommer A, Scott R, Gilbert D (1994) Risk factors for the development of glaucomatous visual field loss in ocular hypertension. Arch Ophthalmol 112:644–649

    Article  PubMed  CAS  Google Scholar 

  219. Calandrella N, Scarsella G, Pescosolido N, Risuleo G (2007) Degenerative and apoptotic events at retinal and optic nerve level after experimental induction of ocular hypertension. Mol Cell Biochem 301:155–163

    Article  PubMed  CAS  Google Scholar 

  220. Harada T, Harada C, Wang YL, Osaka H, Amanai K, Tanaka K, Takizawa S, Setsuie R, Sakurai M, Sato Y, Noda M, Wada K (2004) Role of ubiquitin carboxy terminal hydrolase-L1 in neural cell apoptosis induced by ischemic retinal injury in vivo. Am J Pathol 164:59–64

    Article  PubMed  CAS  Google Scholar 

  221. Yang Y, Fang S, Jensen JP, Weissman AM, Ashwell JD (2000) Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 288:874–877

    Article  PubMed  CAS  Google Scholar 

  222. Ozawa Y, Kurihara T, Sasaki M, Ban N, Yuki K, Kubota S, Tsubota K (2011) Neural degeneration in the retina of the streptozotocin-induced type 1 diabetes model. Exp Diabetic Res 2011:108328, 7 pp.

  223. Ozawa Y, Kurihara T, Tsubota K, Okano H (2011) Regulation of posttranscriptional modification as a possible therapeutic approach for retinal neuroprotection. J Ophthalmol 2011:506137, 8 pp.

  224. Curtis TM, Hamilton R, Yong PH, McVicar CM, Berner A, Pringle R, Uchida K, Nagai R, Brockbank S, Stitt AW (2010) Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products. Diabetologia 54:690–698

    Article  PubMed  CAS  Google Scholar 

  225. Pennathur S, Heinecke JW (2004) Mechanisms of oxidative stress in diabetes: implications for the pathogenesis of vascular disease and antioxidant therapy. Front Biosci 9:565–574

    Article  PubMed  CAS  Google Scholar 

  226. Van Reyk DM, Gillies MC, Davies MJ (2003) The retina: oxidative stress and diabetes. Redox Rep 8:187–192

    Article  PubMed  CAS  Google Scholar 

  227. Fernandes R, Hosoya K, Pereira P (2011) Reactive oxygen species downregulate glucose transport system in retinal endothelial cells. Am J Physiol Cell Physiol 300:C927–C936

    Article  PubMed  CAS  Google Scholar 

  228. Shiels IA, Zhang S, Ambler J, Taylor SM (1998) Vascular leakage stimulates phenotype alteration in ocular cells, contributing to the pathology of proliferative vitreoretinopathy. Med Hypotheses 50:113–117

    Article  PubMed  CAS  Google Scholar 

  229. Jewell UR, Kvietikova I, Scheid A, Bauer C, Wenger RH, Gassmann M (2001) Induction of HIF-1α in response to hypoxia is instantaneous. FASEB J 15:1312–1314

    PubMed  CAS  Google Scholar 

  230. Pe'er J, Shweiki D, Itin A, Hemo I, Gnessin H, Keshet E (1995) Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab Investig 72:638–645

    PubMed  Google Scholar 

  231. Wang GL, Semenza GL (1996) Molecular basis of hypoxia-induced erythropoietin expression. Curr Opin Hematol 3:156–162

    Article  PubMed  CAS  Google Scholar 

  232. Hu J, Discher DJ, Bishopric NH, Webster KA (1998) Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. Biochem Biophys Res Commun 245:894–899

    Article  PubMed  CAS  Google Scholar 

  233. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-α to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472

    Article  PubMed  CAS  Google Scholar 

  234. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468

    Article  PubMed  CAS  Google Scholar 

  235. DeNiro M, Alsmadi O, Al-Mohanna F (2009) Modulating the hypoxia-inducible factor signaling pathway as a therapeutic modality to regulate retinal angiogenesis. Exp Eye Res 89:700–717

    Article  PubMed  CAS  Google Scholar 

  236. Yeh HI, Rothery S, Dupont E, Coppen SR, Severs NJ (1998) Individual gap junction plaques contain multiple connexins in arterial endothelium. Circ Res 83:1248–1263

    Article  PubMed  CAS  Google Scholar 

  237. Fernandes R, Girão H, Pereira P (2004) High glucose down-regulates intercellular communication in retinal endothelial cells by enhancing degradation of connexin 43 by a proteasome-dependent mechanism. J Biol Chem 279:27219–27224

    Article  PubMed  CAS  Google Scholar 

  238. Starke-Reed PE, Oliver CN (1989) Protein oxidation and proteolysis during aging and oxidative stress. Arch Biochem Biophys 275:559–567

    Article  PubMed  CAS  Google Scholar 

  239. Carney JM, Starke-Reed PE, Oliver CN, Landum RW, Cheng MS, Wu JF, Floyd RA (1991) Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone. Proc Natl Acad Sci U S A 88:3633–3636

    Article  PubMed  CAS  Google Scholar 

  240. Stadtman ER (1992) Protein oxidation and aging. Science 257:1220–1224

    Article  PubMed  CAS  Google Scholar 

  241. Agarwal S, Sohal RS (1994) Aging and proteolysis of oxidized proteins. Arch Biochem Biophys 309:24–28

    Article  PubMed  CAS  Google Scholar 

  242. Kliffen M, De Jong PT, Luider TM (1995) Protein analysis of human maculae in relation to age-related maculopathy. Lab Investig 73:267–272

    PubMed  CAS  Google Scholar 

  243. Ishibashi T, Murata T, Hangai M, Nagai R, Horiuchi S, Lopez PF, Hinton DR, Ryan SJ (1998) Advanced glycation end products in age-related macular degeneration. Arch Ophthalmol 116:1629–1632

    PubMed  CAS  Google Scholar 

  244. Stolzing A, Grune T (2001) The proteasome and its function in the ageing process. Clin Exp Dermatol 26:566–572

    Article  PubMed  CAS  Google Scholar 

  245. Cai J, Nelson KC, Wu M, Sternberg P Jr, Jones DP (2000) Oxidative damage and protection of the RPE. Prog Retin Eye Res 19:205–221

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Research at the authors' laboratory is supported by the Instituto de Salud Carlos III (grant ref. PI09/1623, to J.M.-N.). L.C. was the recipient of a predoctoral contract from the Universidad de Alicante.

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  1. Julián Esteve-Rudd

    Present address: Jules Stein Eye Research Institute, UCLA School of Medicine, Los Angeles, CA, 90095, USA

Authors and Affiliations

  1. Departamento de Fisiología, Genética y Microbiología, Facultad de Ciencias, Universidad de Alicante, 03080, Alicante, Spain

    Laura Campello, Julián Esteve-Rudd, Nicolás Cuenca & José Martín-Nieto

  2. Instituto Multidisciplinar para el Estudio del Medio ‘Ramón Margalef,’, Universidad de Alicante, 03080, Alicante, Spain

    Nicolás Cuenca & José Martín-Nieto

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  1. Laura Campello
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  2. Julián Esteve-Rudd
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  4. José Martín-Nieto
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Correspondence to José Martín-Nieto.

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Campello, L., Esteve-Rudd, J., Cuenca, N. et al. The Ubiquitin–Proteasome System in Retinal Health and Disease. Mol Neurobiol 47, 790–810 (2013). https://doi.org/10.1007/s12035-012-8391-5

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