Imbalances in the eye lens proteome are linked to cataract formation

Schmid, Philipp W. N.; Lim, Nicole C. H.; Peters, Carsten; Back, Katrin Christiane; Bourgeois, Benjamin; Pirolt, Franz; Richter, Bettina; Peschek, Jirka; Puk, Oliver; Amarie, Oana V.; Dalke, Claudia; Haslbeck, Martin; Weinkauf, Sevil; Madl, Tobias; Graw, Jochen; Büchner, Johannes

doi:10.1038/s41594-020-00543-9

Cited by 32 publications

(31 citation statements)

References 57 publications

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“…Additional studies are required to address whether calcium precipitates and crystallin aggregates interact with each other during cataract formation in Cx46KO lenses. A recent study suggests that the imbalance of lens proteins causes lens opacity 51 . Major causes of light scattering in dense nuclear cataracts may be associated with crystallin degradation mediated by calcium activated calpains and lens protein imbalance, while calcium precipitates are likely contributing to some light scattering in restricted areas with accumulated calcium precipitates.…”

Section: Discussionmentioning

confidence: 99%

Quantitative X-ray tomographic analysis reveals calcium precipitation in cataractogenesis

Parkinson

Feng

et al. 2021

Sci Rep

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Cataracts, named for pathological light scattering in the lens, are known to be associated with increased large protein aggregates, disrupted protein phase separation, and/or osmotic imbalances in lens cells. We have applied synchrotron phase contrast X-ray micro-computed tomography to directly examine an age-related nuclear cataract model in Cx46 knockout (Cx46KO) mice. High-resolution 3D X-ray tomographic images reveal amorphous spots and strip-like dense matter precipitates in lens cores of all examined Cx46KO mice at different ages. The precipitates are predominantly accumulated in the anterior suture regions of lens cores, and they become longer and dense as mice age. Alizarin red staining data confirms the presence of calcium precipitates in lens cores of all Cx46KO mice. This study indicates that the spatial and temporal calcium precipitation is an age-related event associated with age-related nuclear cataract formation in Cx46KO mice, and further suggests that the loss of Cx46 promotes calcium precipitates in the lens core, which is a new mechanism that likely contributes to the pathological light scattering in this age-related cataract model.

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Section: Discussionmentioning

confidence: 99%

Quantitative X-ray tomographic analysis reveals calcium precipitation in cataractogenesis

Parkinson

Feng

et al. 2021

Sci Rep

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“…Among these causes, aging is the most common cause of cataract formation in which the association of α-crystallin to the eye lens's fiber cell plasma membrane increases progressively [59][60][61][62][63][64][65]. With age and at the onset of cataract formation, water-soluble α-crystallin slowly depletes to the insoluble aggregates [61,63,64,[66][67][68][69]; however, the nature of such insoluble aggregates is not well characterized [63,[67][68][69][70][71][72][73][74]. In the human lens nucleus, the most pronounced conversion of soluble to insoluble α-crystallin and the corresponding conversion of soluble to insoluble high molecular weight (HMW) protein occurs after the age of 40 [63,67,68].…”

Section: Introductionmentioning

confidence: 99%

Association of Alpha-Crystallin with Fiber Cell Plasma Membrane of the Eye Lens Accompanied by Light Scattering and Cataract Formation

Timsina

Mainali

2021

Membranes

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α-crystallin is a major protein found in the mammalian eye lens that works as a molecular chaperone by preventing the aggregation of proteins and providing tolerance to stress in the eye lens. These functions of α-crystallin are significant for maintaining lens transparency. However, with age and cataract formation, the concentration of α-crystallin in the eye lens cytoplasm decreases with a corresponding increase in the membrane-bound α-crystallin, accompanied by increased light scattering. The purpose of this review is to summarize previous and recent findings of the role of the: 1) lens membrane components, i.e., the major phospholipids (PLs) and sphingolipids, cholesterol (Chol), cholesterol bilayer domains (CBDs), and the integral membrane proteins aquaporin-0 (AQP0; formally MIP26) and connexins, and 2) α-crystallin mutations and post-translational modifications (PTMs) in the association of α-crystallin to the eye lens’s fiber cell plasma membrane, providing thorough insights into a molecular basis of such an association. Furthermore, this review highlights the current knowledge and need for further studies to understand the fundamental molecular processes involved in the association of α-crystallin to the lens membrane, potentially leading to new avenues for preventing cataract formation and progression.

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“…Throughout life, transparency of the lens must be maintained to prevent cataract. 1 In the absence of vasculature, metabolites are hypothesized to convect through the lens by a microcirculation system (MCS) where metabolite influx at the poles proceeds towards the inner nucleus and outflow proceeds through the equatorial region of the lens. In the proposed system, flux is established by a sodium gradient near the equatorial epithelium and water is transported through membranes by aquaporin and gap junction proteins.…”

Section: Introductionmentioning

confidence: 99%

Data Independent Acquisition Mass Spectrometry of the Human Lens Enhances Spatiotemporal Measurement of Fiber Cell Aging

Cantrell

Schey

2021

Preprint

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The ocular lens proteome undergoes post-translational and progressive degradation as fiber cells age. The oldest fiber cells and the proteins therein are present at birth and are retained through death. Transparency of the lens is maintained in part by the high abundance crystallin family proteins (up to 300 mg/mL), which establishes a high dynamic range of protein abundance. As a result, previous Data Dependent Analysis (DDA) measurements of the lens proteome are less equipped to identify the lowest abundance proteins. In an attempt to probe more deeply into the lens proteome, we measured the insoluble lens proteome of an 18-year-old human with DDA and newer Data Independent Analysis (DIA) methods. By applying library free DIA search methods, 4,564 protein groups, 48,474 peptides and 5,577 deamidation sites were detected: significantly outperforming the quantity of identifications in using DDA and Pan-Human DIA library searches. Finally, by segmenting the lens into multiple fiber cell-age related regions, we uncovered cell-age resolved changes in proteome composition and putative function.

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Imbalances in the eye lens proteome are linked to cataract formation

Cited by 32 publications

References 57 publications

Quantitative X-ray tomographic analysis reveals calcium precipitation in cataractogenesis

Quantitative X-ray tomographic analysis reveals calcium precipitation in cataractogenesis

Association of Alpha-Crystallin with Fiber Cell Plasma Membrane of the Eye Lens Accompanied by Light Scattering and Cataract Formation

Data Independent Acquisition Mass Spectrometry of the Human Lens Enhances Spatiotemporal Measurement of Fiber Cell Aging

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