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Modified Proteins leads to Cataracts
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Deposition of energy leading to occurrence of cataracts||adjacent||Moderate||Low||Vinita Chauhan (send email)||Open for citation & comment|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
The maintenance of the correct structure and location of lens proteins is crucial for the proper refraction of light in the eye. Any modifications to the proteins of the lens can result in a reduction in lens transparency and cataract formation through the mechanism of protein aggregation (Zhao et al., 2015). Cataracts develop as a result of increased opacity of the lens, leading to reduced visual acuity (Moreau & King, 2012). Under normal conditions, lens proteins work to support the eye through chaperones, gap junctional, and structural functions (Ghosh & Chauhan, 2019; NCRP, 2016). Light enters the eye and passes through the crystallin proteins of the lens, which are responsible for 90% of the proteins in a mature lens. These proteins are carefully arranged as to limit their interference with the light, and the lens cells remove their organelles once they are mature to reduces light-scattering (Moreau & King, 2012; Toyama & Hetzer, 2013). Proteins play other roles in the creation of a transparent medium. Beta- and γ-crystallins are structural proteins that ensure the proper inter-protein interactions occur for the maintenance of nuclear transparency, and alpha crystallin proteins chaperone other proteins, including beta- and γ-crystallins, around the lens (Ghosh & Chauhan, 2019; Toyama & Hetzer, 2013). Lens epithelial cells (LEC) rely on proteins, such as connexin43, to act as phenotypic markers to help organize the cells within the lens following proliferation, preventing the cells from improperly layering within the eye. LECs are packed with crystallin proteins. If the connexin43 proteins are altered, that would impair their ability to help organize the LECs properly, resulting in all the proteins found within those LECs to be disoriented compared to the proteins of neighbouring cells (Berthoud et al., 2014). This improper layering of the cells leads to modified transparency in the lens as a result of the disorganization of the many crystallin proteins within the LEC. Connexin proteins typically join chaperone proteins in a complex and repair misfolded proteins (NCRP, 2016). Proteins can be modified from exposure to stressors, and depending on the type of protein, the alteration will also differ. Following modification, proteins will be unable to correctly perform their roles within the lens, such as preventing aggregation via proper chaperone and structural actions. (Ghosh & Chauhan, 2019; Toyama & Hetzer, 2013; NCRP, 2016). Protein aggregation occurs, which is worsened by the inability of the proteins to form complexes to repair themselves, and this leads to reduced lens transparency and increased cataract incidence.
Evidence Collection Strategy
The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.
Evidence Supporting this KER
Overall Weight of Evidence: Moderate
There is strong biological plausibility to support the link between modified proteins and cataracts. A review focusing on modified proteins and cataracts is particularly relevant as it discusses different types of protein modifications, and the resulting effect on increased human lens opacity (Truscott, 2005). Several other studies discuss multiple types of protein alterations that can cause increased cataracts/lens opacity, often attributed to improper protein function (Hamada et al., 2014; NCRP, 2016; Ghosh & Chauhan, 2019). Currently, the majority of the empirical evidence to support this relationship is derived from studies conducted in adult male subjects, therefore there is limited opportunity to comment on sex or age effects on this relationship (Fujii et al., 1986; Menard et al., 1986). There is also limited information for taxonomic comparisons of rats, humans, and mice related to modified proteins leading to cataracts, with only one paper listed for each species. However, it is evident that all three species have evidence to support the causal connectivity of this relationship (Menard et al., 1986; Truscott, 2005; Fujii et al., 1986).
Once lens fiber cells are damaged, and the intracellular proteins are modified, these modifications are permanent, as the cells lack the organelles needed to undergo protein turnover (Toyama & Hetzer, 2013). These protein modifications can in turn cause protein aggregation, which are high molecular weight proteins, and these can modify the multi-layering of cells (Bron et al., 2000; Moreau & King, 2012; NCRP, 2016). Among the different types of amino acids, tryptophan, histidine, and cysteine are all at risk for modifications from oxidative processes (Balasubramanian, 2000). Oxidized proteins can have modified water-solubility (Hamada et al., 2014; Moreau & King, 2012). The protein content in the lens of the eye needs to be optimal to ensure that the lens transparency can appropriately contribute to the refractive medium of the lens, meaning that the water solubility of proteins is crucial and can dictate the development of lens opacities. Proteins can become water-insoluble when they undergo post-translational modifications, shifting the solubility fraction of the lens proteins (Hamada et al., 2014). They are unable to aggregate while in their natural water-soluble state and must first undergo modifications to decrease solubility and generate a build-up of proteins (Moreau & King, 2012). Alpha-crystalline proteins, when modified, are unable to chaperone other proteins to the correct locations, aggravating the protein aggregation in the eye (Blakely et al., 2010; Uwineza et al., 2019). The binding of these chaperone proteins to the molten globule region of other proteins leads to the formation of high molecular weight proteins, a common protein type seen in cataract patients (NCRP, 2016; Truscott, 2005; Moreau & King, 2012). High-molecular-weight crystalline aggregation causes light to scatter at a higher rate than normal, increasing lens opacity (Uwineza et al., 2019; Bron et al., 2000; Toyama & Hetzer, 2013). Furthermore, when connexin proteins, which form intercellular channels between LECs and lens fiber cells (Tjahjono et al., 2020), are unable to perform their function, the LECs will improperly layer. Modifications to these proteins has been linked to human cataract development (NCRP, 2016).
Uncertainties and Inconsistencies
Known modulating factors
|Modulating Factor (MF)||MF Specification||Effect(s) on the KER||Reference(s)|
|Age||≥ 40 years old (human) has higher incidence of lens opacity||Proteins naturally change and degrade over time however they do not get removed from within the lens’ center. This leads to a higher level of modified protein accumulation within the lens in older individuals. Protein accumulation/aggregation is linked to light scattering and cataracts.||Hains & Truscott, 2010; NCRP, 2016|
|5-cholesten-3b,25-diol (VP1-001)||Administration of compound||VP1-001 reversed α-crystallin aggregation in vivo, resulting in decreased lens opacity.||Molnar et al., 2019; Wang et al., 2022|
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
This KER is plausible in all life stages, sexes, and organisms that have a clear lens for vision. The majority of the evidence is from in vivo studies (adult mice, and rats) and human cohorts. No in vitro evidence was found to support the relationship.
Balasubramanian, D. (2000), “Ultraviolet Radiation and Cataract”, Journal of Ocular Pharmacology and Therapeutics, Vol.16/3, Mary Ann Liebert Inc, Larchmont, https://doi.org/10.1089/JOP.2000.16.285.
Berthoud, V. et al. (2014), “Roles and regulation of lens epithelial cell connexins”, FEBS Letters, Vol. 588/8, Elsevier, England, https://doi.org/10.1016/j.febslet.2013.12.024
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Bron, A. et al. (2000), “The Ageing Lens”, Ophthalmologica, Vol.214, Karger Publishers, Basel, https://doi.org/10.1159/000027475.
Fujii, N. et al. (1986), “D-Amino Acid in Irradiated and Aged Mouse”, Journal of Radiation Research, Vol.27, Oxford University Press, Oxford, https://doi.org/10.1269/JRR.27.183.
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Hamada, N. et al. (2014), “Emerging issues in radiogenic cataracts and cardiovascular disease”, Journal of Radiation Research, Vol.55/5, Oxford University Press, Oxford, https://doi.org/10.1093/jrr/rru036.
Hains, B. and R. Truscott. (2010), “Age-dependent deamidation of lifelong proteins in the human lens”, Investigative Ophthalmology and Visual Science, Vol.51/6, Association for Research in Vision and Ophthalmology, Rockville, https://doi.org/10.1167/iovs.09-4308.
Kozbenko, T. et al. (2022), “Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example”, International Journal of Radiation Biology, 1–12. https://doi.org/10.1080/09553002.2022.2110306
Menard, T. et al. (1986), “Radioprotection against cataract formation by WR-77913 in gamma-irradiated rats”, International Journal of Radiation Oncology Biology Physics, Vol.12, Elsevier, Amsterdam, https://doi.org/10.1016/0360-3016(86)90199-9.
Molnar, K. S. et al. (2019), "Mechanism of action of VP1-001 in cryAB(R120G)-associated and age-related cataracts”, Investigative Ophthalmology & Visual Science, Vol. 60/10, The Association for Research in Vision and Ophthalmology, United States, https://doi.org/ 10.1167/iovs.18-25647
Moreau, K. and J. King. (2012), “Protein misfolding and aggregation in cataract disease and prospects for prevention”, Trends in Molecular Medicine, Vol.18/5, Elsevier Ltd, London, https://doi.org/10.1016/j.molmed.2012.03.005.
NCRP (2016), “Guidance on radiation dose limits for the lens of the eye”, NCRP Commentary, Vol.26, National Council on Radiation Protection and Measurements Publications, Bethesda.
Tjahjono, N. et al. (2020), “Connexin 50-R205G mutation perturbs lens epithelial cell proliferation and differentiation”, Investigative Ophthalmology & Visual Science, Vol. 61/3, The Association for Research in Vision and Ophthalmology, United States, https://doi.org/10.1167/iovs.61.3.25
Toyama, B. and M. Hetzer. (2013), “Protein homeostasis: Live long, won't prosper”, Nature Reviews Molecular Cell Biology, Vol.14/1, Nature Portfolio, Berlin, https://doi.org/10.1038/nrm3496.
Truscott, R. (2005), “Age-related nuclear cataract - Oxidation is the key”, Experimental Eye Research, Vol.80/5, Academic Press Inc, Cambridge, https://doi.org/10.1016/J.EXER.2004.12.007.
Uwineza, A. et al. (2019), “Cataractogenic load – A concept to study the contribution of ionizing radiation to accelerated aging in the eye lens”, Mutation Research-Reviews in Mutation Research, Vol.779, Elsevier, Amsterdam, https://doi.org/10.1016/J.MRREV.2019.02.004.
Wang, K. et al. (2022), “Oxysterol compounds in mouse mutant αA and αB-crystallin lenses ca improve the optical properties of the lens”, Investigative Ophthalmology & Visual Science, Vol. 63/5, The Association for Research in Vision and Ophthalmology, United States, https://doi.org/10.1167/iovs.63.5.15
Zhao, L. et al. (2015), “Lanosterol reverses protein aggregation in cataracts”, Nature, Vol.523, Nature Portfolio, Berlin, https://doi.org/10.1038/nature14650.