Proteases in eye development and disease

Wride, Michael A.; Geatrell, Jenny; Guggenheim, Jeremy A.

doi:10.1002/bdrc.20063

Cited by 53 publications

(46 citation statements)

References 120 publications

(126 reference statements)

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“…At present, there appears to be no clear evidence linking calpains and other lenticular proteases (Swanson et al, 1981(Swanson et al, , 1985Wride et al, 2006) with these crystallin cleavages. The absence of significant proteolytic activity in adult lenses suggests that these LMW peptides may be generated through nonenzymatic cleavage of crystallins.…”

Section: Discussionmentioning

confidence: 98%

Localization of low molecular weight crystallin peptides in the aging human lens using a MALDI mass spectrometry imaging approach

McArthur

Aquilina

2010

Experimental Eye Research

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This article was originally published as Su, S.P., McArthur, J.D., Aquilina, J.A., Localization of low molecular weight crystallin peptides in the aging human lens using a MALDI mass spectrometry imaging approach, Experimental Eye Research, 91(1), 2010, 97-103. Original item available here Localization of low molecular weight crystallin peptides in the aging human lens using a MALDI mass spectrometry imaging approach AbstractLow molecular weight (LMW) peptides, derived from the breakdown of the major eye lens proteins, the crystallins, accumulate in the human lens with age. These LMW peptides are associated with age-related lens opacity and cataract, with some shown to inhibit the chaperone activity of α-crystallin. However, the mechanism(s) giving rise to the production of these peptides, as well as their distribution within the lens, are not well understood. In this study, we have mapped the distribution of these crystallin-derived peptides present in human lenses of different ages using matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS). Our data showed that most of these LMW peptides emerge in the lens at early middle-age, with peptides greater than 1778 Da in mass being confined to the water insoluble fractions, and to a lesser extent the water soluble fractions of older lenses. MALDI-IMS analyses showed that four peptides, derived from αA-, αB-and γS crystallins, were confined to the lens nuclear fibre cells upon emergence during early middle-age, but were present in both the cortex and nucleus of old lenses. In contrast, another major peptide, derived from the C-terminal breakdown of βA3-crystallin, was present in the cortical and nuclear regions of both young and old lenses. A comparison between age-matched cataractous and non-cataractous lenses showed no distinct differences in LMW peptide profiles, indicating that although cataract may be a potential consequence caused by the emergence of these peptides, it does not contribute directly to the peptide-generating process. AbstractLow molecular weight (LMW) peptides, derived from the breakdown of the major eye lens proteins, the crystallins, accumulate in the human lens with age. These LMW peptides are associated with age-related lens opacity and cataract, with some shown to inhibit the chaperone activity of α-crystallin. However, the mechanism(s) giving rise to the production of these peptides, as well as their distribution within the lens, are not well understood. In this study, we have mapped the distribution of these crystallin-derived peptides present in human lenses of different ages using matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS).Our data showed that most of these LMW peptides emerge in the lens at early middle-age, with peptides greater than 1778 Da in mass being confined to the water insoluble fractions, and to a lesser extent the water soluble fractions of older lenses.MALDI-IMS analyses showed that four peptides, derived from αA-, αB-and γS-crystallins, were confined to t...

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Section: Discussionmentioning

confidence: 98%

Localization of low molecular weight crystallin peptides in the aging human lens using a MALDI mass spectrometry imaging approach

McArthur

Aquilina

2010

Experimental Eye Research

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“…Occasionally, it is the part of the normal lens maturation process (2). It may be due to the activation of lens proteolytic enzymes (17,20,33). Nonenzymatic mechanisms are also likely to generate crystallin fragments (34).…”

Section: Discussionmentioning

confidence: 99%

Significance of Interactions of Low Molecular Weight Crystallin Fragments in Lens Aging and Cataract Formation

Santhoshkumar

Udupa

Raju

et al. 2008

Journal of Biological Chemistry

110

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Analysis of aged and cataract lenses shows the presence of increased amounts of crystallin fragments in the high molecular weight aggregates of water-soluble and water-insoluble fractions. However, the significance of accumulation and interaction of low molecular weight crystallin fragments in aging and cataract development is not clearly understood. In this study, 23 low molecular mass (<3.5-kDa) peptides in the urea-soluble fractions of young, aged, and aged cataract human lenses were identified by mass spectroscopy. Two peptides, ␣B-(1-18) (MDIAIHHPWIRRPFFPFH) and ␤A3/A1-(59 -74) (SD(N)AYHIERLMSFRPIC), present in aged and cataract lens but not young lens, and a third peptide, ␥S-(167-178) (SPAVQSFRRIVE) present in all three lens groups were synthesized to study the effects of interaction of these peptides with intact ␣-, ␤-, and ␥-crystallins and alcohol dehydrogenase, a protein used in aggregation studies. Interaction of ␣B-(1-18) and ␤A3/A1-(59 -74) peptides increased the scattering of light by ␤-and ␥-crystallin and alcohol dehydrogenase. The ability of ␣-crystallin subunits to function as molecular chaperones was significantly reduced by interaction with ␣B-(1-18) and ␤A3/ A1-(59 -74) peptides, whereas ␥S peptide had no effect on chaperone-like activity of ␣-crystallin. The ␤A3/A1-(59 -74 peptide caused a 5.64-fold increase in ␣B-crystallin oligomeric mass and partial precipitation. Replacing hydrophobic residues in ␣B-(1-18) and ␤A3/A1-(59 -74) peptides abolished their ability to induce crystallin aggregation and light scattering. Our study suggests that interaction of crystallin-derived peptides with intact crystallins could be a key event in age-related protein aggregation in lens and cataractogenesis.

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“…In general, proteases are known to play important roles in lens development and cataract [37]. However, the question as to whether MMPs play a functional role in mediating cataractogenesis has been largely unexplored.…”

Section: Mmp and Ascmentioning

confidence: 99%

Matrix metalloproteinases as mediators of primary and secondary cataracts

West‐Mays

Pino

2007

Expert Review of Ophthalmology

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The matrix metalloproteinases (MMPs) are a family of endopeptidases involved in numerous remodeling and fibrotic disorders. Although MMPs have been shown to play important roles in regenerative and disease processes in many parts of the eye, including the cornea, retina and trabecular meshwork, the role of MMPs in the normal and cataractous lens has only recently been studied. These investigations have shown that multiple MMPs are expressed in the lens and their expression is altered in a number of cataract phenotypes. However, anterior subcapsular cataract and posterior capsular opacification, cataracts of a fibrotic nature, show a particular involvement of MMPs. This review will highlight recent findings that suggest a causative role for MMPs in these fibrotic cataract phenotypes. Keywords cataract; EMT; fibrosis; lens; MMPIs; matrix metalloproteinase Cataract is the leading cause of blindness worldwide despite the availability of effective surgery in the developed countries [1,2]. The etiology of cataract is diverse (see Allen [3] for review) with the majority of cataracts related to aging. Extracapsular cataract extraction provides quick restoration of vision and is the most frequently performed surgical procedure in the developed world, costing over US$3.5 billion each year in the USA alone [4]. However, it is not without its problems and can lead to complications such as the development of secondary cataract (up to 40-50% incidence of patients), also known as posterior capsular opacification (PCO) [5,6]. PCO is a major medical problem with profound consequences to the patient's well-being and is a significant financial burden. PCO is considered a proliferative, fibrotic disorder that involves the aberrant deposition of matrix and wrinkling of the lens capsule [7]. Another cataract type, also of a fibrotic nature, is anterior subcapsular cataract (ASC) [6,8,9]. ASC, unlike PCO, is a primary cataract that occurs when lens epithelial cells (LECs), in situ, are stimulated to transition into myofibroblasts. These fibroblasts form subcapsular plaques directly beneath the lens capsule. Despite these differences, recent evidence has shown that in both cataract phenotypes the matrix metalloproteinases (MMPs), matrix-degrading enzymes, †Author

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Proteases in eye development and disease

Cited by 53 publications

References 120 publications

Localization of low molecular weight crystallin peptides in the aging human lens using a MALDI mass spectrometry imaging approach

Localization of low molecular weight crystallin peptides in the aging human lens using a MALDI mass spectrometry imaging approach

Significance of Interactions of Low Molecular Weight Crystallin Fragments in Lens Aging and Cataract Formation

Matrix metalloproteinases as mediators of primary and secondary cataracts

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