Advertisement

Common Mechanisms for Separate Maculopathies?

  • Elod KortvelyEmail author
  • Marius Ueffing
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)

Abstract

Maculopathies include Mendelian monogenic (familial) as well as complex (sporadic) diseases that primarily afflict the central retina. Although prevalence, onset, inheritance, and clinical manifestation may differ substantially among macular diseases, emerging evidence suggests overlapping pathogenic pathways. We propose here a hypothesis connecting familial and sporadic maculopathies on the basis of overlapping protein networks, which also systematically integrate nongenetic (environmental) risk factors. Based on the function and network connectivity of proteins and metabolites implicated in these maculopathies, three major areas can be outlined: (1) lipid metabolism, (2) the extracellular matrix (ECM), and (3) the complement system. On the physiological level, extracellular deposition of waste products with high lipid content is a characteristic of most maculopathies, suggesting that perturbed lipid metabolism and subsequent deposition of its extracellular components in ECM (e.g., by forming hydrophobic barriers between intra- and extracellular compartments) plays a significant role. Extracellular microanatomical barriers composed of lipoproteinaceous structures (like the Bruch’s membrane) receive protection against degradation through complement factor H (CFH), a critical negative regulator of alternative complement pathway activation. As such, all three areas, primarily defined by genetic association or linkage analysis, may compose a disease network with distinct but interconnected molecular areas. The concept of overlapping disease phenotypes based on overlapping networks and etiologies bears potential to define directions of future research and help to pinpoint candidate genes for maculopathies of unknown origin, where the disease causing mutation has been narrowed down to a chromosomal region harboring a limited number of genes.

Keywords

Maculopathy Maculopathies AMD Familial Sporatic Lipid metabolism Extracellular matrix ECM Complement CFH Risk factors 

References

  1. Antonicelli F, Bellon G, Debelle L et al (2007) Elastin-elastases and inflamm-aging. Curr Top Dev Biol 79:99–155PubMedCrossRefGoogle Scholar
  2. Bernhard D, Moser C, Backovic A et al (2007) Cigarette smoke--an aging accelerator? Exp Gerontol 42:160–165PubMedCrossRefGoogle Scholar
  3. Chen W, Stambolian D, Edwards AO et al (2010) Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A 107:7401–7406PubMedCrossRefGoogle Scholar
  4. Chong NH, Keonin J, Luthert PJ et al (2005) Decreased thickness and integrity of the macular elastic layer of Bruch’s membrane correspond to the distribution of lesions associated with age-related macular degeneration. Am J Pathol 166:241–251PubMedCrossRefGoogle Scholar
  5. Curcio CA, Johnson M, Huang JD et al (2010) Apolipoprotein B-containing lipoproteins in retinal aging and age-related macular degeneration. J Lipid Res 51:451–467PubMedCrossRefGoogle Scholar
  6. Dewan A, Liu M, Hartman S et al (2006) HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314:989–992PubMedCrossRefGoogle Scholar
  7. Edwards AO, Ritter R, 3 rd, Abel KJ et al (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308:421–424PubMedCrossRefGoogle Scholar
  8. Fantini J, Yahi N (2010) Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases. Expert Rev Mol Med 12:e27PubMedCrossRefGoogle Scholar
  9. Imamura Y, Engelbert M, Iida T et al (2010) Polypoidal choroidal vasculopathy: a review. Surv Ophthalmol 55:501–515PubMedCrossRefGoogle Scholar
  10. Just M, Ribera M, Monso E et al (2007) Effect of smoking on skin elastic fibres: morphometric and immunohistochemical analysis. Br J Dermatol 156:85–91PubMedCrossRefGoogle Scholar
  11. Kavanagh D, Richards A, Atkinson J (2008) Complement regulatory genes and hemolytic uremic syndromes. Annu Rev Med 59:293–309PubMedCrossRefGoogle Scholar
  12. Koldamova R, Fitz NF, Lefterov I (2010) The role of ATP-binding cassette transporter A1 in Alzheimer’s disease and neurodegeneration. Biochim Biophys Acta 1801:824–830PubMedGoogle Scholar
  13. Kortvely E, Hauck SM, Duetsch G et al (2010) ARMS2 is a constituent of the extracellular matrix providing a link between familial and sporadic age-related macular degenerations. Invest Ophthalmol Vis Sci 51:79–88PubMedCrossRefGoogle Scholar
  14. Le Fur I, Laumet G, Richard F et al (2010) Association study of the CFH Y402H polymorphism with Alzheimer’s disease. Neurobiol Aging 31:165–166PubMedCrossRefGoogle Scholar
  15. Nordstrom S, Thorburn W (1980) Dominantly inherited macular degeneration (Best’s disease) in a homozygous father with 11 children. Clin Genet 18:211–216PubMedCrossRefGoogle Scholar
  16. Perez VI, Van Remmen H, Bokov A et al (2009) The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell 8:73–75PubMedCrossRefGoogle Scholar
  17. Provis JM, Penfold PL, Cornish EE et al (2005) Anatomy and development of the macula: specialisation and the vulnerability to macular degeneration. Clin Exp Optom 88:269–281PubMedCrossRefGoogle Scholar
  18. Reynolds R, Rosner B, Seddon JM (2010) Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration. Ophthalmology 117:1989–1995PubMedCrossRefGoogle Scholar
  19. Robert L, Robert AM, Fulop T (2008) Rapid increase in human life expectancy: will it soon be limited by the aging of elastin? Biogerontology 9:119–133PubMedCrossRefGoogle Scholar
  20. Segade F (2010) Molecular evolution of the fibulins: implications on the functionality of the elastic fibulins. Gene 464:17–31PubMedCrossRefGoogle Scholar
  21. Shu X, Tulloch B, Lennon A et al (2006) Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5. Hum Mol Genet 15:1680–1689PubMedCrossRefGoogle Scholar
  22. Timmer NM, Kuiperij HB, de Waal RM et al (2010) Do Amyloid-beta-Associated Factors Co-deposit with Abeta in Mouse Models for Alzheimer’s Disease? J Alzheimers DisGoogle Scholar
  23. Weber BH, Vogt G, Pruett RC et al (1994) Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby’s fundus dystrophy. Nat Genet 8:352–356PubMedCrossRefGoogle Scholar
  24. Yanagisawa H, Davis EC (2010) Unraveling the mechanism of elastic fiber assembly: The roles of short fibulins. Int J Biochem Cell Biol 42:1084–1093PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of Experimental OphthalmologyUniversity of TuebingenTuebingenGermany

Personalised recommendations