Advertisement

Protein Misfolding and Potential Therapeutic Treatments in Inherited Retinopathies

  • Lawrence C. S. TamEmail author
  • Anna-Sophia Kiang
  • Matthew Campbell
  • James Keaney
  • G. Jane Farrar
  • Marian M. Humphries
  • Paul F. Kenna
  • Pete Humphries
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)

Abstract

Retinitis pigmentosa (RP) is a group of inherited retinopathies characterized by progressive peripheral vision loss that can subsequently lead to central vision loss. RP is one of the most common causes of registered visual handicap among those of the working age in developed countries, and currently it is estimated to affect 1 in 3,500 people worldwide. At the genetic level, RP is one of the most heterogeneous inherited conditions, segregating in autosomal dominant, recessive, or X-linked recessive modes, with approximately 40 genes having been implicated in the disease pathology (http://www.sph.uth.tmc.edu/RetNet). To date, there is a growing list of destabilizing mutations within retinal-specific or nonspecific genes (e.g., RHO, RPGR, RS1, BBS6, AIPL1, RDS-peripherin, and IMPDH1, etc.) that have been found to cause proteins to misfold and become aggregation-prone with subsequent loss of normal protein functions. In this minireview, we will briefly explore the role protein misfolding plays as a disease mechanism in autosomal dominant RP and also highlight potential therapeutic strategies for inhibiting protein aggregation in the retina.

Keywords

Retinitis pigmentosa Protein misfolding Heat shock protein Rhodopsin IMPDH1 RDS-peripherin Chaperones Gene therapy 

Notes

Acknowledgments

The Ocular Genetics Unit at TCD is supported by grants from Science Foundation Ireland (07-IN.1.B1778); The MRC/HRB (FB06HUM); The Wellcome Trust (083866/2/07/2): Enterprise Ireland (PC/2008/0006); Fighting Blindness Ireland (FB09HUM); IRCSET (G30364/G30409).

References

  1. Adessi C, Soto C (2002) Converting a peptide into a drug: strategies to improve stability and bioavailability. Curr Med Chem 9:963–978PubMedCrossRefGoogle Scholar
  2. Aherne A, Kennan A, Kenna PF et al (2004) On the molecular pathology of neurodegeneration in IMPDH1-based retinitis pigmentosa. Hum Mol Genet 13:641–650PubMedCrossRefGoogle Scholar
  3. Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Rev Neurosci 5:S18–S25CrossRefGoogle Scholar
  4. Bartolini M, Andrisano V (2010) Strategies for the inhibition of protein aggregation in human diseases. ChemBioChem 11:1018–1035PubMedCrossRefGoogle Scholar
  5. Bowne SJ, Sullivan LS, Blanton SH et al (2002) Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa. Hum Mol Genet 11:559–568PubMedCrossRefGoogle Scholar
  6. Bukau B, Weissman J, Horwich A (2006) Molecular chaperones and protein quality control. Cell 125:443–451PubMedCrossRefGoogle Scholar
  7. Conley SM, Stricker HM, Naash MI (2010) Biochemical analysis of phenotypic diversity associated with mutations in codon 244 of the retinal degeneration slow gene. Biochemistry 49:905–911PubMedCrossRefGoogle Scholar
  8. Dryja TP, McGee TL, Reichel E et al (1990) A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 343:364–366PubMedCrossRefGoogle Scholar
  9. Farrar GJ, Kenna P, Jordan SA et al (1991) A three-base-pair deletion in the peripherin-RDS gene in one form of retinitis pigmentosa. Nature 354: 478–480PubMedCrossRefGoogle Scholar
  10. Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426:895–899PubMedCrossRefGoogle Scholar
  11. Gorbatyuk MS, Knox T, LaVail MM et al (2010)Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78. Proc Natl Acad Sci USA 107:5961–5966PubMedCrossRefGoogle Scholar
  12. Guisbert E, Yura T, Rhodius VA (2008) Convergence of molecular, modelling, and systems approaches for an understanding of the Escherichia coli heat shock response. Microbiol Mol Biol Rev 72:545–554PubMedCrossRefGoogle Scholar
  13. Hartl FU, Hayer-Hartl M (2009) Converging concepts of protein folding in vitro and in vivo. Nature Struct Mol Biol 16:574–581CrossRefGoogle Scholar
  14. Hashimoto M, Hsu LJ, Xia Y (1999a) Oxidative stress induces amyloid-like aggregate formation of NACP/alpha-synuclein in vitro. Neuroreport 10:717–721PubMedCrossRefGoogle Scholar
  15. Hashimoto M, Takeda A, Hsu LJ (1999b) Role of cytochrome c as a stimulator of alpha-synuclein aggregation in Lewy body disease. J Biol Chem 274:28849–28852PubMedCrossRefGoogle Scholar
  16. Hiroyama S, Yamazaki Y, Kitamura A (2007) MKKS is a centrosome-shuttling protein degraded by disease-causing mutations via CHIP-mediated ubiquitination. Mol Biol Cell 19:899–911CrossRefGoogle Scholar
  17. Illing ME, Rajan RS, Bence NF (2002) A rhodopsin mutant linked to autosomal dominant retinitis pigmentosa is prone to aggregate and interacts with the ubiquitin proteasome system. J Biol Chem 277:34150–34160PubMedCrossRefGoogle Scholar
  18. Kennan A, Aherne A, Palfi A et al (2002) Identification of an IMPDH1 mutation in autosomal dominant retinitis pigmentosa (RP10) revealed following comparative microarray analysis of transcripts derived from retinas of wild-type and Rho(2/2) mice. Hum Mol Genet 11, 547–557PubMedCrossRefGoogle Scholar
  19. Mendes HF, van der Spuy J, Chapple JP et al (2005) Mechanisms of cell death in rhodopsin retinitis pigmentosa: implications for therapy. Trends Mol Med 11:177–185PubMedCrossRefGoogle Scholar
  20. O’Reilly M, Palfi A, Chadderton N et al (2007) RNA interference-mediated suppression and replacement of human rhodopsin in vivo. Am J Hum Genet 81:127–135PubMedCrossRefGoogle Scholar
  21. Olsson JE, Gordon JW, Pawlyk BS et al (1992) Transgenic mice with a rhodopsin mutation (Pro23His): a mouse model of autosomal dominant retinitis pigmentosa. Neuron 9:815–830PubMedCrossRefGoogle Scholar
  22. Ono K, Yamada J (2006) Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. J Neurochem 97:115–115CrossRefGoogle Scholar
  23. Pratt WB, Toft DO (2003) Regulation of signalling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med 228:111–133Google Scholar
  24. Raichur A, Vali S, Gorin F (2006) Dynamic modelling of alpha-synuclein aggregation for the sporadic and genetic forms of Parkinson’s disease. Neuroscience 142:859–870PubMedCrossRefGoogle Scholar
  25. Rajan RS, Kopito RR (2005) Suppression of wild-type rhodopsin maturation by mutants linked to autosomal dominant retinitis pigmentosa. J Biol Chem 280:1284–1291PubMedCrossRefGoogle Scholar
  26. Rocha S, Cardoso I, Borner H (2009) Design and biological activity of beta-sheet breaker peptide conjugates. Biochem Biophys Res Commun 380:397–401PubMedCrossRefGoogle Scholar
  27. Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10:S10–S17.49Google Scholar
  28. Rubinsztein DC (2006) The roles of intracellular protein degradation pathways in neurodegeneration. Nature 443:780–786PubMedCrossRefGoogle Scholar
  29. Saliba RS, Munro PMG, Luthert PJ (2002) The cellular fate of mutant rhodopsin: quality control, degradation and aggresome formation. J Cell Sci 115:2907–2918PubMedGoogle Scholar
  30. Sittler A, Lurz R, Lueder G et al (2001) Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease. Hum Mol Genet 10:1307–1315PubMedCrossRefGoogle Scholar
  31. Sloan LA, Fillmore MC, Churcher I (2009) Small-molecule modulation of cellular chaperones to treat protein misfolding disorders. Curr Opin Drug Discov Dev 12:666–681Google Scholar
  32. Soto C, Kascsak RJ, Saborio GP (2000) Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides. Lancet 355:192–197PubMedCrossRefGoogle Scholar
  33. Surguchev A, Surguchov A (2009) Conformational diseases: Looking into the eyes. Brain Res Bull 81:12–24CrossRefGoogle Scholar
  34. Tam LC, Kiang AS, Campbell M et al (2010) Prevention of autosomal dominant retinitis pigmentosa by systemic drug therapy targeting heat shock protein 90 (Hsp90). Hum Mol Genet 19:4421–4436PubMedCrossRefGoogle Scholar
  35. Tam LC, Kiang AS, Kennan A et al (2008) Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10). Hum Mol Genet 17:2084–2100PubMedCrossRefGoogle Scholar
  36. Warrick JM, Chan HY, Gray-Board GL et al (1999) Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 23:425–428PubMedCrossRefGoogle Scholar
  37. Wisniewski T, Sadowski M (2008) Preventing beta-amyloid fibrillization and deposition: beta-sheet breakers and pathological chaperone inhibitors. BMC Neurosci 9:S5PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Lawrence C. S. Tam
    • 1
    Email author
  • Anna-Sophia Kiang
    • 1
  • Matthew Campbell
    • 1
  • James Keaney
    • 1
  • G. Jane Farrar
    • 1
  • Marian M. Humphries
    • 1
  • Paul F. Kenna
    • 1
  • Pete Humphries
    • 1
  1. 1.Department of Genetics, The Ocular Genetics UnitTrinity College DublinDublin 2Ireland

Personalised recommendations