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Quantification of thioether-linked glutathione modifications in human lens proteins.
Wang Z, Schey KL
(2018) Exp Eye Res 175: 83-89
MeSH Terms: Adolescent, Alanine, Aminobutyrates, Cataract, Cellular Senescence, Chromatography, Liquid, Crystallins, Cysteine, Glutathione, Humans, Lens, Crystalline, Middle Aged, Protein Processing, Post-Translational, Serine, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Sulfides, Threonine, Tissue Donors, Young Adult
Show Abstract · Added April 4, 2019
Dehydroalanine (DHA) and dehydrobutyrine (DHB) intermediates, formed through β-elimination, induce protein irreversible glutathionylation and protein-protein crosslinking in human lens fiber cells. In total, irreversible glutathionylation was detected on 52 sites including cysteine, serine and threonine residues in 18 proteins in human lenses. In this study, the levels of GSH modification on three serine residues and four cysteine residues located in seven different lens proteins isolated from different regions and different aged lenses were quantified. The relative levels of modification (modified/nonmodified) were site-specific and age-related, ranging from less than 0.05% to about 500%. The levels of modification on all of the sites quantified in the lens cortex increased with age and GSH modification also increased from cortex to outer nucleus region suggesting an age-related increase of modification. The levels of modification on sites located in stable regions of the proteins such as Cys117 of βA3, Cys80 of βB1 and Cys27 of γS, continued increasing in inner nucleus, but modification on sites located in regions undergoing degradation with age decreased in the inner nucleus suggesting GSH modified proteins were more susceptible to further modification. Irreversible GSH modification in cataract lenses was typically higher than in age-matched normal lenses, but the difference did not reach statistical significance for a majority of sites, with the exception Cys117 of βA3 crystallin in WSF. Except for S59 of αA and αB crystallins, GSH modification did not induce protein insolubility suggesting a possible role for this modification in protection from protein-protein crosslinking.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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MeSH Terms
Spatial distributions of glutathione and its endogenous conjugates in normal bovine lens and a model of lens aging.
Nye-Wood MG, Spraggins JM, Caprioli RM, Schey KL, Donaldson PJ, Grey AC
(2017) Exp Eye Res 154: 70-78
MeSH Terms: Aging, Animals, Cataract, Cattle, Crystallins, Disease Models, Animal, Glutathione, Lens, Crystalline, Metabolomics, Oxidative Stress, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tandem Mass Spectrometry, Tissue Distribution
Show Abstract · Added April 17, 2017
Glutathione (GSH) is the archetypal antioxidant, and plays a central role in the protection of the ocular lens from cataract formation. High levels of GSH are maintained in the transparent lens, but with advancing age, GSH levels fall in the lens nucleus relative to outer cortical cells, thereby exposing the nucleus of the lens to the damaging effects of oxygen radicals, which ultimately leads to age-related nuclear (ARN) cataract. Under normal conditions, GSH also forms endogenous conjugates to detoxify the lens of reactive cellular metabolites and to maintain cell homeostasis. Due to the intrinsic gradient of lens fibre cell age, the lens contains distinct regions with different metabolic requirements for GSH. To investigate the impact of fibre cell and lens aging on the varied roles that GSH plays in the lens, we have utilised high mass resolution MALDI mass spectrometry profiling and imaging analysis of lens tissue sections. High Dynamic Range (HDR)-MALDI FTICR mass spectrometry was used as an initial screening method to detect regional differences in lens metabolites from normal bovine lenses and in those subjected to hyperbaric oxygen as a model of lens aging. Subsequent MALDI imaging analysis was used to spatially map GSH and its endogenous conjugates throughout all lenses. Accurate mass measurement by MALDI FTICR analysis and LC-MS/MS mass spectrometry of lens region homogenates were subsequently used to identify endogenous GSH conjugates. While the distribution and relative abundance of GSH-related metabolic intermediates involved in detoxification pathways remained relatively unchanged upon HBO treatment, those involved in its antioxidant function were altered under conditions of oxidative stress. For example, reduced glutathione levels were decreased in the lens cortex while oxidised glutathione levels were elevated in the lens outer cortex upon HBO treatment. Interestingly, cysteineglutathione disulfide, was detected in the inner cortex of the normal lens, but was greatly decreased in the HBO-treated lenses. These results contribute to our understanding of the multiple roles that GSH plays in maintenance of lens transparency and in the age-related metabolic changes that lead to lens cataract formation.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Identification and Functional Assessment of Age-Dependent Truncations to Cx46 and Cx50 in the Human Lens.
Slavi N, Wang Z, Harvey L, Schey KL, Srinivas M
(2016) Invest Ophthalmol Vis Sci 57: 5714-5722
MeSH Terms: Aging, Cataract, Cell Membrane Permeability, Cells, Cultured, Connexins, Humans, Lens, Crystalline, Membrane Glycoproteins, Middle Aged, Patch-Clamp Techniques, Tandem Mass Spectrometry
Show Abstract · Added May 6, 2017
Purpose - Many proteins in the lens undergo extensive posttranslational modifications (PTMs) with age, leading to alterations in their function. The extent to which lens gap junction proteins, Cx46 and Cx50, accumulate PTMs with aging is not known. In this study, we identified truncations in Cx46 and Cx50 in the human lens using mass spectrometry. We also examined the effect of truncations on channel function using electrophysiological measurements.
Methods - Human lenses were dissected into cortex, outer nucleus, and nucleus regions, and fiber cell membranes were subjected to trypsin digestion. Tryptic peptides were analyzed by liquid chromatography (LC)-electrospray tandem mass spectrometry (ESI/MS/MS). Effects of truncations on channel conductance, permeability, and gating were assessed in transfected cells.
Results - Cleavage sites were identified in the C-terminus, the cytoplasmic loop, and the N-terminus of Cx46 and Cx50. Levels of C-terminal truncations, which were found at residues 238 to 251 in Cx46 and at residues 238 to 253 and 274 to 284 in Cx50, were similar in different lens regions. In contrast, levels of truncations in cytoplasmic loop and N-terminal domains of Cx46 and Cx50 increased dramatically from outer cortex to nucleus. Most of the C-terminally truncated proteins were functional, whereas truncations in the cytoplasmic loop did not result in the formation of functional channels.
Conclusions - Accumulation of cytoplasmic loop and N-terminal truncations in the core might lead to decreases in coupling with age. This reduction is expected to lead to an increase in intracellular calcium and a decrease in levels of glutathione in the nucleus. These changes may ultimately lead to age-related nuclear cataracts.
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11 MeSH Terms
Expression of Cataract-linked γ-Crystallin Variants in Zebrafish Reveals a Proteostasis Network That Senses Protein Stability.
Wu SY, Zou P, Fuller AW, Mishra S, Wang Z, Schey KL, Mchaourab HS
(2016) J Biol Chem 291: 25387-25397
MeSH Terms: Animals, Cataract, Lens Capsule, Crystalline, Mice, Mutation, Protein Aggregates, Zebrafish, Zebrafish Proteins, alpha-Crystallin A Chain, gamma-Crystallins
Show Abstract · Added May 6, 2017
The refractivity and transparency of the ocular lens is dependent on the stability and solubility of the crystallins in the fiber cells. A number of mutations of lens crystallins have been associated with dominant cataracts in humans and mice. Of particular interest were γB- and γD-crystallin mutants linked to dominant cataracts in mouse models. Although thermodynamically destabilized and aggregation-prone, these mutants were found to have weak affinity to the resident chaperone α-crystallin in vitro To better understand the mechanism of the cataract phenotype, we transgenically expressed different γD-crystallin mutants in the zebrafish lens and observed a range of lens defects that arise primarily from the aggregation of the mutant proteins. Unlike mouse models, a strong correlation was observed between the severity and penetrance of the phenotype and the level of destabilization of the mutant. We interpret this result to reflect the presence of a proteostasis network that can "sense" protein stability. In the more destabilized mutants, the capacity of this network is overwhelmed, leading to the observed increase in phenotypic penetrance. Overexpression of αA-crystallin had no significant effects on the penetrance of lens defects, suggesting that its chaperone capacity is not limiting. Although consistent with the prevailing hypothesis that a chaperone network is required for lens transparency, our results suggest that αA-crystallin may not be efficient to inhibit aggregation of lens γ-crystallin. Furthermore, our work implicates additional inputs/factors in this underlying proteostasis network and demonstrates the utility of zebrafish as a platform to delineate mechanisms of cataract.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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10 MeSH Terms
Socioeconomic Disparities in Cataract Prevalence, Characteristics, and Management.
Mundy KM, Nichols E, Lindsey J
(2016) Semin Ophthalmol 31: 358-63
MeSH Terms: Cataract, Cataract Extraction, Health Status Disparities, Humans, Prevalence, Social Class, Vision Disorders
Show Abstract · Added August 31, 2017
PURPOSE - To review the current literature on socioeconomic disparities relationship with cataract prevalence, characteristics, and management.
SUMMARY - Cataracts are an important cause of preventable visual impairment in both the developing and industrialized world. Cataract surgery is a highly effective operation with an excellent risk profile. Furthermore, cataract surgery has been shown to have significant positive functional, social, and economic implications for patients. Several medical conditions have been shown to have correlation with socioeconomic factors and cataract is among several forms of visual impairment that demonstrate this relationship. Disparities in prevalence, clinical characteristics, and management are documented in the ophthalmic literature. A better understanding of these socioeconomic factors and their clinical relevance is critical to alleviating the burden of cataract-related visual impairment in an aging population.
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7 MeSH Terms
Imaging mass spectrometry of the visual system: Advancing the molecular understanding of retina degenerations.
Bowrey HE, Anderson DM, Pallitto P, Gutierrez DB, Fan J, Crouch RK, Schey KL, Ablonczy Z
(2016) Proteomics Clin Appl 10: 391-402
MeSH Terms: Cataract, Glaucoma, Humans, Lipid Metabolism, Lipofuscin, Macular Degeneration, Optical Imaging, Retina, Retinoids, Rhodopsin, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added February 8, 2016
Visual sensation is fundamental for quality of life, and loss of vision to retinal degeneration is a debilitating condition. The eye is the only part of the central nervous system that can be noninvasively observed with optical imaging. In the clinics, various spectroscopic methods provide high spatial resolution images of the fundus and the developing degenerative lesions. However, the currently utilized tools are not specific enough to establish the molecular underpinnings of retinal diseases. In contrast, mass spectrometric imaging (MSI) is a powerful tool to identify molecularly specific disease indicators and classification markers. This technique is particularly well suited to the eye, where molecular information can be correlated with clinical data collected via noninvasive diagnostic imaging modalities. Recent studies during the last few recent years have uncovered a plethora of new spatially defined molecular information on several vision-threatening diseases, including age-related macular degeneration, Stargardt disease, glaucoma, cataract, as well as lipid disorders. Even though MS inside the eye cannot be performed noninvasively, by linking diagnostic and molecular information, these studies are the first step toward the development of smart ophthalmic diagnostic and surgical tools. Here, we provide an overview of current approaches applying MSI technology to ocular pathology.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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11 MeSH Terms
MALDI Imaging Mass Spectrometry Spatially Maps Age-Related Deamidation and Truncation of Human Lens Aquaporin-0.
Wenke JL, Rose KL, Spraggins JM, Schey KL
(2015) Invest Ophthalmol Vis Sci 56: 7398-405
MeSH Terms: Adult, Aging, Aquaporins, Cataract, Eye Proteins, Female, Fourier Analysis, Humans, Lens, Crystalline, Male, Middle Aged, Protein Processing, Post-Translational, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tandem Mass Spectrometry, Young Adult
Show Abstract · Added February 15, 2016
PURPOSE - To spatially map human lens Aquaporin-0 (AQP0) protein modifications, including lipidation, truncation, and deamidation, from birth through middle age using matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS).
METHODS - Human lens sections were water-washed to facilitate detection of membrane protein AQP0. We acquired MALDI images from eight human lenses ranging in age from 2 months to 63 years. In situ tryptic digestion was used to generate peptides of AQP0 and peptide images were acquired on a 15T Fourier transform ion cyclotron resonance (FTICR) mass spectrometer. Peptide extracts were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and database searched to identify peptides observed in MALDI imaging experiments.
RESULTS - Unmodified, truncated, and fatty acid-acylated forms of AQP0 were detected in protein imaging experiments. Full-length AQP0 was fatty acid acylated in the core and cortex of young (2- and 4-month) lenses. Acylated and unmodified AQP0 were C-terminally truncated in older lens cores. Deamidated tryptic peptides (+0.9847 Da) were mass resolved from unmodified peptides by FTICR MS. Peptide images revealed differential localization of un-, singly-, and doubly-deamidated AQP0 C-terminal peptide (239-263). Deamidation was present at 4 months and increases with age. Liquid chromatography-MS/MS results indicated N246 undergoes deamidation more rapidly than N259.
CONCLUSIONS - Results indicated AQP0 fatty acid acylation and deamidation occur during early development. Progressive age-related AQP0 processing, including deamidation and truncation, was mapped in human lenses as a function of age. The localization of these modified AQP0 forms suggests where AQP0 functions may change throughout lens development and aging.
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15 MeSH Terms
Role of αA-crystallin-derived αA66-80 peptide in guinea pig lens crystallin aggregation and insolubilization.
Raju M, Mooney BP, Thakkar KM, Giblin FJ, Schey KL, Sharma KK
(2015) Exp Eye Res 132: 151-60
MeSH Terms: Animals, Cataract, Disease Models, Animal, Guinea Pigs, Hyperbaric Oxygenation, Lens, Crystalline, Mass Spectrometry, Molecular Chaperones, Peptide Fragments, alpha-Crystallins
Show Abstract · Added February 12, 2015
Earlier we reported that low molecular weight (LMW) peptides accumulate in aging human lens tissue and that among the LMW peptides, the chaperone inhibitor peptide αA66-80, derived from α-crystallin protein, is one of the predominant peptides. We showed that in vitro αA66-80 induces protein aggregation. The current study was undertaken to determine whether LMW peptides are also present in guinea pig lens tissue subjected to hyperbaric oxygen (HBO) in vivo. The nuclear opacity induced by HBO in guinea pig lens is the closest animal model for studying age-related cataract formation in humans. A LMW peptide profile by mass spectrometry showed the presence of an increased amount of LMW peptides in HBO-treated guinea pig lenses compared to age-matched controls. Interestingly, the mass spectrometric data also showed that the chaperone inhibitor peptide αA66-80 accumulates in HBO-treated guinea pig lens. Following incubation of synthetic chaperone inhibitor peptide αA66-80 with α-crystallin from guinea pig lens extracts, we observed a decreased ability of α-crystallin to inhibit the amorphous aggregation of the target protein alcohol dehydrogenase and the formation of large light scattering aggregates, similar to those we have observed with human α-crystallin and αA66-80 peptide. Further, time-lapse recordings showed that a preformed complex of α-crystallin and αA66-80 attracted additional crystallin molecules to form even larger aggregates. These results demonstrate that LMW peptide-mediated cataract development in aged human lens and in HBO-induced lens opacity in the guinea pig may have common molecular pathways.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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10 MeSH Terms
Macular pigment optical density in a healthy Chinese population.
Ji Y, Zhang X, Wu K, Su Y, Zuo C, Chen H, Li M, Wen F
(2015) Acta Ophthalmol 93: e550-5
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Aging, Asian Continental Ancestry Group, Body Mass Index, Cataract, Child, Child, Preschool, China, Cross-Sectional Studies, Densitometry, Female, Healthy Volunteers, Humans, Lutein, Macular Pigment, Male, Middle Aged, Retina, Surveys and Questionnaires, Zeaxanthins
Show Abstract · Added January 20, 2015
PURPOSE - To measure the macular pigment optical density (MPOD) values in a healthy Chinese population using the one-wavelength reflectometry method and to investigate the relationships of MPOD with age, sex, body mass index (BMI), smoking and lens opacities.
METHODS - A total of 441 healthy participants, aged 3-81 years old (242 male and 199 female subjects), were enrolled in this study. Demographic and lifestyle data were recorded based on physical examinations and questionnaires. Lens opacities were measured according to the Lens Opacities Classification System III (LOCS III). MPOD values were measured at 7° of eccentricity, using the one-wavelength reflectometry method (Visucam 200; Carl Zeiss Meditec). MPOD values were reported in parameters including 'max' and 'mean' optical density (OD). The original MPOD values without automated correction were used for analysis.
RESULTS - The average values were 0.303 ± 0.097 d.u. (initials of density units) for the max OD and 0.109 ± 0.031 d.u. for the mean OD. A significant inverse relationship was found between age and MPOD (for max OD, β = -0.716, p < 0.001; for mean OD, β = -0.669, p < 0.001). Participants with no lens opacities had higher MPOD values than those with moderate lens opacities (p < 0.001). The MPOD values were not associated with sex, BMI or smoking status.
CONCLUSION - MPOD within 7° of eccentricity, as measured by one-wavelength reflectometry, was found to decrease with increasing age in a healthy Chinese population, and lens opacities had an impact on these measurements. These results provide a reference value for future studies in the Chinese population.
© 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.
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23 MeSH Terms
Electronic medical records and genomics (eMERGE) network exploration in cataract: several new potential susceptibility loci.
Ritchie MD, Verma SS, Hall MA, Goodloe RJ, Berg RL, Carrell DS, Carlson CS, Chen L, Crosslin DR, Denny JC, Jarvik G, Li R, Linneman JG, Pathak J, Peissig P, Rasmussen LV, Ramirez AH, Wang X, Wilke RA, Wolf WA, Torstenson ES, Turner SD, McCarty CA
(2014) Mol Vis 20: 1281-95
MeSH Terms: Age Factors, Aged, Aged, 80 and over, Algorithms, Cataract, Databases, Nucleic Acid, Electronic Health Records, Female, Fructose-Bisphosphate Aldolase, Genetic Markers, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Health Care Costs, Humans, MAP Kinase Kinase Kinase 1, MEF2 Transcription Factors, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, United States
Show Abstract · Added March 14, 2018
PURPOSE - Cataract is the leading cause of blindness in the world, and in the United States accounts for approximately 60% of Medicare costs related to vision. The purpose of this study was to identify genetic markers for age-related cataract through a genome-wide association study (GWAS).
METHODS - In the electronic medical records and genomics (eMERGE) network, we ran an electronic phenotyping algorithm on individuals in each of five sites with electronic medical records linked to DNA biobanks. We performed a GWAS using 530,101 SNPs from the Illumina 660W-Quad in a total of 7,397 individuals (5,503 cases and 1,894 controls). We also performed an age-at-diagnosis case-only analysis.
RESULTS - We identified several statistically significant associations with age-related cataract (45 SNPs) as well as age at diagnosis (44 SNPs). The 45 SNPs associated with cataract at p<1×10(-5) are in several interesting genes, including ALDOB, MAP3K1, and MEF2C. All have potential biologic relationships with cataracts.
CONCLUSIONS - This is the first genome-wide association study of age-related cataract, and several regions of interest have been identified. The eMERGE network has pioneered the exploration of genomic associations in biobanks linked to electronic health records, and this study is another example of the utility of such resources. Explorations of age-related cataract including validation and replication of the association results identified herein are needed in future studies.
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22 MeSH Terms