Retinal Degeneration and Cellular Suicide

  • Wai Gin Fong
  • Catherine TsilfidisEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)


Retinal degenerative diseases are a heterogeneous group of dystrophies defined by progressive loss of vision due to photoreceptor cell death. They are caused by genetic mutation, nutrient deprivation, oxidative stress, or inflammation. A common thread among these conditions is the activation of programmed cell death (PCD) during the disease process. Although PCD is vital for the proper development and maintenance of the retina, the inappropriate activation of cellular suicide pathways upsets the balance of death/life signals within a cell and can ultimately lead to the untimely death of sensitive cells such as photoreceptors. The goal of many researchers is to reestablish this balance through the removal of PCD triggers or blocking of PCD pathways. We will examine gene therapy approaches that directly target PCD pathways and some successes in protecting the retina from degeneration.


Apoptosis Autophagy Retinitis pigmentosa XIAP Retinal ­degeneration Programmed cell death Retina 


  1. Berger AB, Sexton KB, Bogyo M (2006) Commonly used caspase inhibitors designed based on substrate specificity profiles lack selectivity. Cell Res 16:961–963PubMedCrossRefGoogle Scholar
  2. Bode C, Wolfrum U (2003) Caspase-3 inhibitor reduces apototic photoreceptor cell death during inherited retinal degeneration in tubby mice. Mol Vis 9:144–150PubMedGoogle Scholar
  3. Diaz-Troya S, Perez-Perez ME, Florencio FJ et al (2008) The role of TOR in autophagy regulation from yeast to plants and mammals. Autophagy 4:851–865PubMedGoogle Scholar
  4. Doonan F, Cotter TG (2004) Apoptosis: a potential therapeutic target for retinal degenerations. Curr Neurovasc Res 1:41–53PubMedCrossRefGoogle Scholar
  5. Doonan F, Donovan M, Cotter TG (2003) Caspase-independent photoreceptor apoptosis in mouse models of retinal degeneration. J Neurosci 23:5723–5731PubMedGoogle Scholar
  6. Eisenberg-Lerner A, Bialik S, Simon HU et al (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16:966–975PubMedCrossRefGoogle Scholar
  7. Farber DB (1995) From mice to men: the cyclic GMP phosphodiesterase gene in vision and disease. The Proctor Lecture. Invest Ophthalmol Vis Sci 36:263–275PubMedGoogle Scholar
  8. Feng Z, Zhang H, Levine AJ et al (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102:8204–8209PubMedCrossRefGoogle Scholar
  9. Galban S, Duckett CS (2010) XIAP as a ubiquitin ligase in cellular signaling. Cell Death Differ 17:54–60PubMedCrossRefGoogle Scholar
  10. Glick D, Barth S, Macleod KF (2010) Autophagy: cellular and molecular mechanisms. J Pathol 221:3–12PubMedCrossRefGoogle Scholar
  11. Gozuacik D, Bialik S, Raveh T et al (2008) DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death. Cell Death Differ 15:1875–1886PubMedCrossRefGoogle Scholar
  12. Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368:1795–1809PubMedCrossRefGoogle Scholar
  13. Hietakangas V, Cohen SM (2009) Regulation of tissue growth through nutrient sensing. Annu Rev Genet 43:389–410PubMedCrossRefGoogle Scholar
  14. Hughes EH, Schlichtenbrede FC, Murphy CC et al (2004) Minocycline delays photoreceptor death in the rds mouse through a microglia-independent mechanism. Exp Eye Res 78:1077–1084PubMedCrossRefGoogle Scholar
  15. Jomary C, Neal MJ, Jones SE (2001) Characterization of cell death pathways in murine retinal neurodegeneration implicates cytochrome c release, caspase activation, and bid cleavage. Mol Cell Neurosci 18:335–346PubMedCrossRefGoogle Scholar
  16. Katai N, Yoshimura N (1999) Apoptotic retinal neuronal death by ischemia-reperfusion is executed by two distinct caspase family proteases. Invest Ophthalmol Vis Sci 40:2697-2705PubMedGoogle Scholar
  17. Klionsky DJ (2005) The molecular machinery of autophagy: unanswered questions. J Cell Sci 118:7–18PubMedCrossRefGoogle Scholar
  18. Lamkanfi M, Declercq W, Depuydt B et al (2003) The Caspase Family. In: Los M, Walczak H (eds) Caspases: Their Role in Cell Death and Cell Survival. Landes Bioscience and Kluwer Academic, New YorkGoogle Scholar
  19. Leonard KC, Petrin D, Coupland SG et al (2007) XIAP protection of photoreceptors in animal models of retinitis pigmentosa. PLoS One 2:e314PubMedCrossRefGoogle Scholar
  20. Li ZY, Milam AH (1995) Apoptosis in retinitis pigmentosa. In: Anderson R, LaVail M, Hollyfield J (eds) Degenerative Diseases of the Retina. Plenum Press, New YorkGoogle Scholar
  21. Liang C, Feng P, Ku B et al (2006) Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol 8:688–699PubMedCrossRefGoogle Scholar
  22. Liston P, Fong WG, Korneluk RG (2003) The inhibitors of apoptosis: there is more to life than Bcl2. Oncogene 22:8568–8580PubMedCrossRefGoogle Scholar
  23. Liu C, Li Y, Peng M et al (1999) Activation of caspase-3 in the retina of transgenic rats with the rhodopsin mutation s334ter during photoreceptor degeneration. J Neurosci 19:4778–4785PubMedGoogle Scholar
  24. Lohr HR, Kuntchithapautham K, Sharma AK et al (2006) Multiple, parallel cellular suicide mechanisms participate in photoreceptor cell death. Exp Eye Res 83:380–389PubMedCrossRefGoogle Scholar
  25. Massey A, Kiffin R, Cuervo AM (2004) Pathophysiology of chaperone-mediated autophagy. Int J Biochem Cell Biol 36:2420–2434PubMedCrossRefGoogle Scholar
  26. Mizukoshi S, Nakazawa M, Sato K et al (2010) Activation of mitochondrial calpain and release of apoptosis-inducing factor from mitochondria in RCS rat retinal degeneration. Exp Eye Res 91:353–361PubMedCrossRefGoogle Scholar
  27. Mizushima N (2007) Autophagy: process and function. Genes Dev 21:2861–2873PubMedCrossRefGoogle Scholar
  28. Nir I, Kedzierski W, Chen J et al (2000) Expression of Bcl-2 protects against photoreceptor degeneration in retinal degeneration slow (rds) mice. J Neurosci 20:2150–2154PubMedGoogle Scholar
  29. Pereira NA, Song Z (2008) Some commonly used caspase substrates and inhibitors lack the specificity required to monitor individual caspase activity. Biochem Biophys Res Commun 377:873–877PubMedCrossRefGoogle Scholar
  30. Petrin D, Baker A, Brousseau J et al (2003a) XIAP protects photoreceptors from n-methyl-n-nitrosourea-induced retinal degeneration. Adv Exp Med Biol 533:385–393PubMedCrossRefGoogle Scholar
  31. Petrin D, Baker A, Coupland SG et al (2003b) Structural and functional protection of photoreceptors from MNU-induced retinal degeneration by the X-linked inhibitor of apoptosis. Invest Ophthalmol Vis Sci 44:2757–2763PubMedCrossRefGoogle Scholar
  32. Punzo C, Kornacker K, Cepko CL (2009) Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa. Nat Neurosci 12:44–52PubMedCrossRefGoogle Scholar
  33. Renwick J, Narang MA, Coupland SG et al (2006) XIAP-mediated neuroprotection in retinal ischemia. Gene Ther 13:339–347PubMedCrossRefGoogle Scholar
  34. Sanges D, Marigo V (2006) Cross-talk between two apoptotic pathways activated by endoplasmic reticulum stress: differential contribution of caspase-12 and AIF. Apoptosis 11:1629–1641PubMedCrossRefGoogle Scholar
  35. Singh M, Savitz SI, Hoque R et al (2001) Cell-specific caspase expression by different neuronal phenotypes in transient retinal ischemia. J Neurochem 77:466–475PubMedCrossRefGoogle Scholar
  36. Suzuki Y, Nakabayashi Y, Takahashi R (2001) Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proc Natl Acad Sci U S A 98:8662–8667PubMedCrossRefGoogle Scholar
  37. Wei Y, Pattingre S, Sinha S et al (2008) JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30:678–688PubMedCrossRefGoogle Scholar
  38. Yoshizawa K, Kiuchi K, Nambu H et al (2002) Caspase-3 inhibitor transiently delays inherited retinal degeneration in C3H mice carrying the rd gene. Graefes Arch Clin Exp Ophthalmol 240:214–219PubMedCrossRefGoogle Scholar
  39. Zacks DN, Zheng QD, Han Y et al (2004) FAS-mediated apoptosis and its relation to intrinsic pathway activation in an experimental model of retinal detachment. Invest Ophthalmol Vis Sci 45:4563–4569PubMedCrossRefGoogle Scholar
  40. Zacks DN, Hanninen V, Pantcheva M et al (2003) Caspase activation in an experimental model of retinal detachment. Invest Ophthalmol Vis Sci 44:1262–1267PubMedCrossRefGoogle Scholar
  41. Zadro-Lamoureux LA, Zacks DN, Baker AN et al (2009) XIAP effects on retinal detachment-induced photoreceptor apoptosis [corrected]. Invest Ophthalmol Vis Sci 50:1448–1453PubMedCrossRefGoogle Scholar
  42. Zeiss CJ, Neal J, Johnson EA (2004) Caspase-3 in postnatal retinal development and degeneration. Invest Ophthalmol Vis Sci 45:964–970PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Ottawa Hospital Research InstituteOttawa General HospitalOttawaCanada
  2. 2.Department of Cellular and Molecular MedicineUniversity of OttawaOttawaCanada

Personalised recommendations