Genotype, Age, Genetic Background, and Sex Influence <i>Epha2</i>-Related Cataract Development in Mice

Dave, Alpana; Craig, Jamie E; Alamein, Mohammad A.; Skrzypiec, Karina; Beltz, Justin; Pfaff, Annalise; Burdon, Kathryn P.; Erçal, Nuran; Iongh, Robb U. de; Sharma, Shilpi

doi:10.1167/iovs.62.12.3

Cited by 5 publications

(8 citation statements)

References 60 publications

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“…However, its early diagnosis and understanding of the correlated events certainly may decrease the risk of blindness and assist in its therapy. Risk factors such as age, breed, gender, environment, genetics, and previous systemic diseases (metabolic diseases, diabetes mellitus, renal impairment, and obesity) should also be considered 16–18 …”

Section: Introductionmentioning

confidence: 99%

“…Risk factors such as age, breed, gender, environment, genetics, and previous systemic diseases (metabolic diseases, diabetes mellitus, renal impairment, and obesity) should also be considered. [16][17][18] The pathogeny of the cataract involves the participation of several free radical-mediated oxidative events that are associated with gross and irreversible alterations in lens metabolism. 11,19,20 This may be associated with aggregation of lenticular proteins, increase in high molecular weight and insoluble proteins, decrease in the relative amount of soluble proteins, and altered functioning of metabolic pumps and ion and oxygen concentration.…”

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confidence: 99%

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Evaluation of the ratio of different major and trace elements in the lens of dogs with cataract

Jezler

Magalhães

Silva

et al. 2023

Veterinary Ophthalmology

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BackgroundUnderstanding the elements that support cataract development and searching for available therapeutic methods is essential for scientific and social interest. For that purpose, the role of trace elements has been investigated in this study to better understand the development of cataracts in dogs.ObjectiveThe aim of this study was to evaluate the ratio of the major and trace elements by X‐ray fluorescence spectrometry in dog cataract lenses to contribute to diagnostic, non‐surgical, and ophthalmological preventive data.MethodsA single lens with a cataract from each of a total of 88 dogs (cataract group) and a healthy lens from each of 6 dogs (control group) were evaluated. The elements calcium (Ca), iron (Fe), copper (Cu), zinc (Zn), magnesium (Mg), manganese (Mn), and potassium (K) were analyzed by energy dispersive X‐ray fluorescence and X‐ray microfluorescence.ResultsThe results indicated an increase of Ca, Fe, Cu, and Zn, in association with the reabsorption mechanism of hypermature cataracts.ConclusionsThe ratio of elements Ca, Fe, Cu, and Zn was different in cataract lenses than in healthy lenses, and our results may support the development of therapeutic strategies for cataracts in dogs. The Ca concentrations were distinct in the cataract development stages, and the Fe concentration was relatively higher in males when compared to females. Finally, this research stands out with a particular contribution to the understanding of both cataract formation and prevention.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Evaluation of the ratio of different major and trace elements in the lens of dogs with cataract

Jezler

Magalhães

Silva

et al. 2023

Veterinary Ophthalmology

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“…The first report of the lens phenotype in EphA2 −/− mice revealed cortical cataracts that progressed to whole cataracts and lens rupture with age ( Table 2 ) ( Jun et al, 2009 ). These KO animals were in the FVB/NJ genetic background, and EphA2 proteins were sequestered through gene trapping ( Mitchell et al, 2001 ; Guo et al, 2006 ), leading to the formation of aggregates in these EphA2 −/− lenses ( Dave et al, 2021 ). A member of the heat shock protein family, Hsp25, was found to be significantly upregulated in these EphA2 −/− lenses ( Jun et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

“…The partial translated EphA2 ectodomain is bound to a reporter protein, β-galactosidase, that traps the fusion protein in the cytoplasm and forms aggregates. The aggregates trigger a moderate unfolded-protein response (UPR) ( Jun et al, 2009 ; Dave et al, 2021 ). A second gene trapping EphA2 −/− mouse line in the mixed 129/SvJ:C57BL/6J genetic background was also examined ( Jun et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

“…A recent report showed that when the exon 5/intron 6 gene-trapping EphA2 −/− mice were backcrossed to the C57BL/6J genetic background, the KO lenses developed progressively more severe cortical cataracts, but the opacity did not progress to whole cataracts or lens rupture ( Dave et al, 2021 ). Thus, it is likely that genetic modifiers in the C57BL/6J background affect cataract severity and phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Roles of Eph-Ephrin Signaling in the Eye Lens Cataractogenesis, Biomechanics, and Homeostasis

Murugan

Cheng

2022

Front. Cell Dev. Biol.

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The eye lens is responsible for fine focusing of light onto the retina, and its function relies on tissue transparency and biomechanical properties. Recent studies have demonstrated the importance of Eph-ephrin signaling for the maintenance of life-long lens homeostasis. The binding of Eph receptor tyrosine kinases to ephrin ligands leads to a bidirectional signaling pathway that controls many cellular processes. In particular, dysfunction of the receptor EphA2 or the ligand ephrin-A5 lead to a variety of congenital and age-related cataracts, defined as any opacity in the lens, in human patients. In addition, a wealth of animal studies reveal the unique and overlapping functions of EphA2 and ephrin-A5 in lens cell shape, cell organization and patterning, and overall tissue optical and biomechanical properties. Significant differences in lens phenotypes of mouse models with disrupted EphA2 or ephrin-A5 signaling indicate that genetic modifiers likely affect cataract phenotypes and progression, suggesting a possible reason for the variability of human cataracts due to Eph-ephrin dysfunction. This review summarizes the roles of EphA2 and ephrin-A5 in the lens and suggests future avenues of study.

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Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

Chen,

Shi,

et al. 2023

Sig Transduct Target Ther

158

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The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or “proteostasis”. The protein quality control systems involve ER-associated degradation, protein chaperons, and autophagy. ER stress is activated when proteostasis is broken with an accumulation of misfolded and unfolded proteins in the ER. ER stress activates an adaptive unfolded protein response to restore proteostasis by initiating protein kinase R-like ER kinase, activating transcription factor 6, and inositol requiring enzyme 1. ER stress is multifaceted, and acts on aspects at the epigenetic level, including transcription and protein processing. Accumulated data indicates its key role in protein homeostasis and other diverse functions involved in various ocular diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, ocular tumors, ocular surface diseases, and myopia. This review summarizes the molecular mechanisms underlying the aforementioned ocular diseases from an ER stress perspective. Drugs (chemicals, neurotrophic factors, and nanoparticles), gene therapy, and stem cell therapy are used to treat ocular diseases by alleviating ER stress. We delineate the advancement of therapy targeting ER stress to provide new treatment strategies for ocular diseases.

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Genotype, Age, Genetic Background, and Sex Influence Epha2-Related Cataract Development in Mice

Cited by 5 publications

References 60 publications

Evaluation of the ratio of different major and trace elements in the lens of dogs with cataract

Evaluation of the ratio of different major and trace elements in the lens of dogs with cataract

Roles of Eph-Ephrin Signaling in the Eye Lens Cataractogenesis, Biomechanics, and Homeostasis

Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

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