Cholesterol Content Regulates the Interaction of αA-, αB-, and α-Crystallin with the Model of Human Lens-Lipid Membranes

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1923 - 1923

Published: Feb. 5, 2024

α-Crystallin (αABc) is a major protein comprised of αA-crystallin (αAc) and αB-crystallin (αBc) that found in the human eye lens works as molecular chaperone by preventing aggregation proteins providing tolerance to stress. However, with age cataract formation, concentration αABc cytoplasm decreases, corresponding increase membrane-bound αABc. This study uses electron paramagnetic resonance (EPR) spin-labeling method investigate role cholesterol (Chol) Chol bilayer domains (CBDs) binding αAc, αBc, Chol/model lens-lipid (Chol/MHLL) membranes. The maximum percentage membrane surface occupied (MMSO) Chol/MHLL membranes at mixing ratio 0 followed trends: MMSO > ≈ (αABc), indicating higher amount αAc binds these compared αBc an membranes, decreases until it completely diminished 1.5. Ka trend: (αAc), but was close zero mobility near headgroup regions decreased binding, antagonized capacity decrease regions. No significant change order observed, concentrations. Our results show bind differently ratios 0.5, decreasing increasing hydrophobicity region, likely forming hydrophobic barrier for passage polar ionic molecules, including antioxidants (glutathione), creating oxidative environment inside lens, leading development cataracts. all 1.5, high CBDs inhibit formation barriers protecting against formation.

Language: Английский

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Tissue, cellular, and molecular level determinants for eye lens stiffness and elasticity

Frontiers in Ophthalmology, Journal Year: 2024, Volume and Issue: 4

Published: Aug. 8, 2024

The eye lens is a transparent, ellipsoid tissue in the anterior chamber that required for fine focusing of light onto retina to transmit clear image. function tied transparency, refractive index, and biomechanical properties. stiffness elasticity or resilience human allows shape changes during accommodation focus from objects near far. It has long been hypothesized properties with age lead loss accommodative ability need reading glasses age. However, cellular molecular mechanisms influence and/or change remain unclear. Studies mouse models genetic defects at advanced inform us cytoskeletal, structural, morphometric parameters are important stability. In this review, we will explore whether: 1) level changes, including capsule, volume, nucleus 2) alterations, cell packing, suture organization, complex membrane interdigitations, 3) scale modifications, F-actin intermediate filament networks, protein lipids membrane, hydrostatic pressure, overall

Language: Английский

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Generation of Lens Progenitor Cells and Lentoid Bodies from Pluripotent Stem Cells: Novel Tools for Human Lens Development and Ocular Disease Etiology

Cells, Journal Year: 2022, Volume and Issue: 11(21), P. 3516 - 3516

Published: Nov. 6, 2022

In vitro differentiation of human pluripotent stem cells (hPSCs) into specialized tissues and organs represents a powerful approach to gain insight those cellular molecular mechanisms regulating development. Although normal embryonic eye development is complex process, generation ocular organoids specific from has provided invaluable insights the formation lineage-committed progenitor cell populations, signal transduction pathways, self-organization principles. This review provides comprehensive summary recent advances in adenohypophyseal, olfactory, lens placodes, three-dimensional (3D) primitive lenses, “lentoid bodies”, “micro-lenses”. These are produced alone or “community-grown” with other tissues. Lentoid bodies/micro-lenses generated patients carrying mutations crystallin genes demonstrate proof-of-principle that these suitable for mechanistic studies cataractogenesis. Taken together, current emerging advanced methods pave road understand cataract caused by entire spectrum DNA-binding regulatory genes, such as PAX6, SOX2, FOXE3, MAF, PITX3, HSF4, individual crystallins, BFSP1, BFSP2, EPHA2, GJA3, GJA8, LIM2, MIP, TDRD7 represented patients.

Language: Английский

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Prevention of age-related truncation of γ-glutamylcysteine ligase catalytic subunit (GCLC) delays cataract formation

Science Advances, Journal Year: 2024, Volume and Issue: 10(17)

Published: April 26, 2024

A sharp drop in lenticular glutathione (GSH) plays a pivotal role age-related cataract (ARC) formation. Despite recognizing GSH's importance lens defense for decades, its decline with age remains puzzling. Our recent study revealed an truncation affecting the essential GSH biosynthesis enzyme, γ-glutamylcysteine ligase catalytic subunit (GCLC), at aspartate residue 499. Intriguingly, these truncated GCLC fragments compete full-length forming heterocomplex modifier (GCLM) but exhibit markedly reduced enzymatic activity. Crucially, using aspartate-to-glutamate mutation knock-in (D499E-KI) mouse model that blocks truncation, we observed notable delay ARC formation compared to WT mice: Nearly 50% of D499E-KI mice remained cataract-free versus ~20% their 20 months. findings concerning might be key understanding profound reduction age. By halting can rejuvenate levels and considerably postpone onset.

Language: Английский

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Oxidative Stress in Cataract Formation: Is There a Treatment Approach on the Horizon?

Antioxidants, Journal Year: 2024, Volume and Issue: 13(10), P. 1249 - 1249

Published: Oct. 16, 2024

Cataracts, a leading cause of blindness worldwide, are closely linked to oxidative stress-induced damage lens epithelial cells (LECs). Key factors contributing cataract formation include aging, arterial hypertension, and diabetes mellitus. Given the high global prevalence cataracts, burden cataract-related visual impairment is substantial, highlighting need for pharmacological strategies supplement surgical interventions. Understanding molecular pathways involved in stress during development may offer valuable insights designing novel therapeutic approaches. This review explores role formation, focusing on critical mechanisms, such as mitochondrial dysfunction, endoplasmic reticulum stress, loss gap junctions, various cell death LECs. Additionally, we discuss emerging potential targeting options, including antioxidant-based treatments.

Language: Английский

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Measurement of absolute abundance of crystallins in human and αA N101D transgenic mouse lenses using 15N-labeled crystallin standards.

Experimental Eye Research, Journal Year: 2024, Volume and Issue: unknown, P. 110115 - 110115

Published: Oct. 1, 2024

Language: Английский

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Evaluation of cataract formation in fish exposed to environmental radiation at Chernobyl and Fukushima

The Science of The Total Environment, Journal Year: 2023, Volume and Issue: 902, P. 165957 - 165957

Published: Aug. 4, 2023

Recent studies apparently finding deleterious effects of radiation exposure on cataract formation in birds and voles living near Chernobyl represent a major challenge to current protection regulations. This study conducted an integrated assessment cataractogenesis using the most advanced technologies available assess status lenses extracted from fish caught at both Ukraine Fukushima Japan. It was hypothesised that these novel data would reveal positive correlations between dose early indicators formation. The structure, function optical properties were analysed atomic millimetre length scales. We measured short-range order lens crystallin proteins Small Angle X-Ray Scattering (SAXS) SPring-8 DIAMOND synchrotrons, profile graded refractive index generated by proteins, epithelial cell density organisation finally focal each lens. results showed no evidence difference length, densities, indices, interference functions (X-ray diffraction patterns) exposed different doses. could be argued animals natural environment which developed more likely, for example, suffer predation leading survivor bias. But cross-length scale presented here, evaluating small molecular cellular changes (pre-cataract formation) significantly mitigates against this issue.

Language: Английский

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TRPV1‐dependent NKCC1 activation in mouse lens involves integrin and the tubulin cytoskeleton

Journal of Cellular Physiology, Journal Year: 2024, Volume and Issue: 239(11)

Published: July 16, 2024

Abstract Previously we showed hyperosmotic solution caused TRPV1‐dependent NKCC1 activation in the lens by a mechanism that involved ERK1/2 signaling. In various tissues, integrins and cytoskeletal network play role responses to osmotic stress. Here, examined association between of mouse epithelium. Wild‐type (WT) lenses exposed integrin agonist leukadherin‐1 (LA‐1) for 10 min displayed ~33% increase bumetanide‐sensitive rate Rb uptake indicating NKCC activation. Paclitaxel, microtubule stabilizing agent, abolished response. primary cultured epithelium LA‐1 robust response was almost fully suppressed paclitaxel. The TRPV1 capsaicin similar Consistent with an TRPV1, antagonist A889425 prevented as did ERK inhibitor U0126. not from knockout mice. cells stimulus, both were Taken together, findings suggest is associated tubulin cytoskeleton. This aligned observation elicited cytoplasmic calcium rise WT but failed lenses. results are consistent notion LA‐1, or causes channel opening consequent downstream responses.

Language: Английский

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Cumulative asparagine to aspartate deamidation fails to perturb γD‐crystallin structure and stability

Protein Science, Journal Year: 2024, Volume and Issue: 33(8)

Published: July 18, 2024

Abstract Deamidation frequently is invoked as an important driver of crystallin aggregation and cataract formation. Here, we characterized the structural biophysical consequences cumulative Asn to Asp changes in γD‐crystallin. Using NMR spectroscopy, demonstrate that N‐ or C‐terminal domain‐confined fully changed γD‐crystallin exhibits essentially same 1 H‐ 15 N HSQC spectrum wild‐type protein, implying overall structure retained. Only a very small thermodynamic destabilization for variants was noted by chaotropic unfolding, assessment colloidal stability, measuring diffusion interaction parameters, yielded no substantive differences association propensities. Furthermore, using molecular dynamics simulations, significant proteins with iso‐Asp were detected. Our combined results substitution all residues, reflecting extreme case deamidation, did not affect properties This suggests these alone cannot be major determinant driving

Language: Английский

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Cone contrast test-HD: sensitivity and specificity in red–green dichromacy and the impact of age

Journal of the Optical Society of America A, Journal Year: 2023, Volume and Issue: 40(5), P. 849 - 849

Published: March 2, 2023

We report normative cone contrast sensitivity values, right-left eye agreement, and specificity values for the test-HD (CCT-HD). included 100 phakic eyes with color vision normal (CVN) 20 dichromatic (10 protanopia 10 deuteranopia). The CCT-HD was used to measure L, M, S-CCT-HD scores, right left were evaluated agreement using Lin's concordance correlation coefficient (CCC) Bland-Altman analysis investigate of based on diagnosis an anomaloscope device. All types in moderate CCC (L-cone: 0.92, 95% CI, 0.86-0.95; M-cone: 0.91, 0.84-0.94; S-cone: 0.93, 0.88-0.96), whereas plots showed that majority cases 94%; 92%; 92%) fell within limits good agreement. mean±standard error scores 0.6±1.4, 74.7±2.7, 94.6±2.4, respectively; deuteranopia, these 84.0±3.4, 40.8±3.3, 93.0±5.8, age-matched CVN (mean±standard deviation age, 53.1±5.8 years; age range, 45-64 years), 98.5±3.4, 94.8±3.8, 92.3±3.4, respectively, significant differences between groups except score (Bonferroni corrected α=0.0167, p<0.0167). 100% protan deutan diagnosing abnormal those aged 64 however, decreased 65% 55% >65 years. is comparable diagnostic performance 20-64-year-old group. However, results should be interpreted cautiously ≥65 years, as patients are more susceptible acquired deficiencies due yellowing crystalline lens other factors.

Language: Английский

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