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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Adessi C, Soto C (2002) Converting a peptide into a drug: strategies to improve stability and bioavailability. Curr Med Chem 9:963–978
Aherne A, Kennan A, Kenna PF et al (2004) On the molecular pathology of neurodegeneration in IMPDH1-based retinitis pigmentosa. Hum Mol Genet 13:641–650
Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Rev Neurosci 5:S18–S25
Bartolini M, Andrisano V (2010) Strategies for the inhibition of protein aggregation in human diseases. ChemBioChem 11:1018–1035
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 11:559–568
Bukau B, Weissman J, Horwich A (2006) Molecular chaperones and protein quality control. Cell 125:443–451
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 49:905–911
Dryja TP, McGee TL, Reichel E et al (1990) A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 343:364–366
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: 478–480
Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426:895–899
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 107:5961–5966
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 72:545–554
Hartl FU, Hayer-Hartl M (2009) Converging concepts of protein folding in vitro and in vivo. Nature Struct Mol Biol 16:574–581
Hashimoto M, Hsu LJ, Xia Y (1999a) Oxidative stress induces amyloid-like aggregate formation of NACP/alpha-synuclein in vitro. Neuroreport 10:717–721
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 274:28849–28852
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 19:899–911
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 277:34150–34160
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, 547–557
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 11:177–185
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 81:127–135
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 9:815–830
Ono K, Yamada J (2006) Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. J Neurochem 97:115–115
Pratt WB, Toft DO (2003) Regulation of signalling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med 228:111–133
Raichur A, Vali S, Gorin F (2006) Dynamic modelling of alpha-synuclein aggregation for the sporadic and genetic forms of Parkinson’s disease. Neuroscience 142:859–870
Rajan RS, Kopito RR (2005) Suppression of wild-type rhodopsin maturation by mutants linked to autosomal dominant retinitis pigmentosa. J Biol Chem 280:1284–1291
Rocha S, Cardoso I, Borner H (2009) Design and biological activity of beta-sheet breaker peptide conjugates. Biochem Biophys Res Commun 380:397–401
Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10:S10–S17.49
Rubinsztein DC (2006) The roles of intracellular protein degradation pathways in neurodegeneration. Nature 443:780–786
Saliba RS, Munro PMG, Luthert PJ (2002) The cellular fate of mutant rhodopsin: quality control, degradation and aggresome formation. J Cell Sci 115:2907–2918
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 10:1307–1315
Sloan LA, Fillmore MC, Churcher I (2009) Small-molecule modulation of cellular chaperones to treat protein misfolding disorders. Curr Opin Drug Discov Dev 12:666–681
Soto C, Kascsak RJ, Saborio GP (2000) Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides. Lancet 355:192–197
Surguchev A, Surguchov A (2009) Conformational diseases: Looking into the eyes. Brain Res Bull 81:12–24
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 19:4421–4436
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 17:2084–2100
Warrick JM, Chan HY, Gray-Board GL et al (1999) Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 23:425–428
Wisniewski T, Sadowski M (2008) Preventing beta-amyloid fibrillization and deposition: beta-sheet breakers and pathological chaperone inhibitors. BMC Neurosci 9:S5
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).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media, LLC
About this paper
Cite this paper
Tam, L.C.S. et al. (2012). Protein Misfolding and Potential Therapeutic Treatments in Inherited Retinopathies. In: LaVail, M., Ash, J., Anderson, R., Hollyfield, J., Grimm, C. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 723. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-0631-0_72
Download citation
DOI: https://doi.org/10.1007/978-1-4614-0631-0_72
Published:
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4614-0630-3
Online ISBN: 978-1-4614-0631-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)