Probing the changes in gene expression due to α-crystallin mutations in mouse models of hereditary human cataract

Andley, Usha P.; Tycksen, Eric; McGlasson-Naumann, Brittney N.; Hamilton, Paul D.

doi:10.1371/journal.pone.0190817

Cited by 23 publications

(23 citation statements)

References 63 publications

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“…Over 90% of lens proteins are in the crystallin family (3), which maintain clear vision by retaining a high amount of native β-sheet secondary structures. Crystallins remain soluble for decades at high concentrations, since they are not regenerated in the organelle-free lens cells (4,5). While they are stable proteins, over time, UV light and other factors slowly damage crystallins (6), causing aggregation and, ultimately, cataract disease.…”

mentioning

confidence: 99%

Amyloid found in human cataracts with two-dimensional infrared spectroscopy

Alperstein

Ostrander

Zhang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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UV light and other factors damage crystallin proteins in the eye lens, resulting in cataracts that scatter light and affect vision. Little information exists about protein structures within these disease-causing aggregates. We examined postmortem lens tissue from individuals with and without cataracts using 2D infrared (2DIR) spectroscopy. Amyloid β-sheet secondary structure was detected in cataract lenses along with denatured structures. No amyloid structures were found in lenses from juveniles, but mature lenses with no cataract diagnosis also contained amyloid, indicating that amyloid structures begin forming before diagnosis. Light scatters more strongly in regions with amyloid structure, and UV light induces amyloid β-sheet structures, linking the presence of amyloid structures to disease pathology. Establishing that age-related cataracts involve amyloid structures gives molecular insight into a common human affliction and provides a possible structural target for pharmaceuticals as an alternative to surgery.

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mentioning

confidence: 99%

Amyloid found in human cataracts with two-dimensional infrared spectroscopy

Alperstein

Ostrander

Zhang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…An increase in histones in lenses from the αA-R49C mutant mice may be indicative of an increase in nucleosome density, and a functional increase in the histone/DNA ratio may lead to increased amounts of heterochromatin. The increase in histone transcripts in Cryaa -R49C mice suggests that the increase in gene expression of histones may be an early event in cataractogenesis, though the notion that α-crystallin functions as a modulator of the expression of histones has not yet been investigated [16] . Nevertheless, these findings strongly suggest a functional relationship between histones and α-crystallin.…”

Section: Introductionmentioning

confidence: 99%

In vitro interactions of histones and α-crystallin

Hamilton

Andley

2018

Biochemistry and Biophysics Reports

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The aggregation of crystallins in lenses is associated with cataract formation. We previously reported that mutant crystallins are associated with an increased abundance of histones in knock-in and knockout mouse models. However, very little is known about the specific interactions between lens crystallins and histones. Here, we performed in vitro analyses to determine whether α-crystallin interacts with histones directly. Isothermal titration calorimetry revealed a strong histone–α-crystallin binding with a Kd of 4 × 10−7 M, and the thermodynamic parameters suggested that the interaction was both entropy and enthalpy driven. Size-exclusion chromatography further showed that histone–α-crystallin complexes are water soluble but become water insoluble as the concentration of histones is increased. Right-angle light scattering measurements of the water-soluble fractions of histone–α-crystallin mixtures showed a decrease in the oligomeric molecular weight of α-crystallin, indicating that histones alter the oligomerization of α-crystallin. Taken together, these findings reveal for the first time that histones interact with and affect the solubility and aggregation of α-crystallin, indicating that the interaction between α-crystallin and histones in the lens is functionally important.

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“…In the presence of oxidative stress, Hsp27 plays a role as an antioxidant, decreasing the ROS by raising levels of intracellular GSH [28,29]. It has been reported that mutation in HspB1 and/or αB-crystallin are responsible for the development of cataract [30] and are considered as major targets for the development of anti-cataract drugs [31]. We have previously reported that expression of Prdx6, an anti-oxidant protein, is decreased resulting in an increase in ROS in the LECs of SCRs [9].…”

Section: Discussionmentioning

confidence: 99%

Identification of differential gene expression pattern in lens epithelial cells derived from cataractous and non-cataractous lenses of Shumiya cataract rat

Ishida

Shibata²,

Nakamura³

et al. 2020

Preprint

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The Shumiya cataract rat (SCR) is a model for hereditary cataract. Two-third of these rats develop lens opacity within 10-11-weeks. Onset of cataract is attributed to the synergetic effect of lanosterol synthase (Lss) and farnesyl-diphosphate farnesyltransferase 1 (Fdft1) mutant alleles that lead to cholesterol deficiency in the lenses, which in turn adversely affects lens biology including the growth and differentiation of lens epithelial cells (LECs). Nevertheless, the molecular events and changes in gene expression associated with the onset of lens opacity in SCR is poorly understood. In the present study, a microarray-based approach was employed to analyze comparative gene expression changes in LECs isolated from the pre-cataractous and cataractous stages of lenses of 5-, 8-and 10-week-old SCRs. The changes in gene expression observed in microarray results in the LECs were further validated using real-time PCR and western blot analyses. Lens opacity was not observed in 5-week-old rats. However, histological analysis revealed mild dysplasia in the anterior suture and poorly differentiated fiber cells at the bow region.Expression of approximately 100 genes, including major intrinsic protein of lens fiber (MIP and Aquaporin0), deoxyribonuclease II beta (Dnase2b), heat shock protein B1 (Hspb1), and crystallin γ (γCry) B, C, and F were found to be significantly downregulated (0.07-0.5 fold) in rat LECs derived from cataract lenses compared to that in noncataractous lenses (control). Thus, our study aimed to identify the gene expression patterns during cataract formation in SCRs, which may be responsible for cataractogenesis in SCR. We proposed that mutation in lanosterol synthase was responsible for the downregulation of genes associated with lens fiber differentiation, which in turn leads to the formation of cataract in these rats. Our findings may have wider implications in understanding the effect of cholesterol deficiency and the role of cholesterol-lowering therapeutics on cataractogenesis. 3

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Probing the changes in gene expression due to α-crystallin mutations in mouse models of hereditary human cataract

Cited by 23 publications

References 63 publications

Amyloid found in human cataracts with two-dimensional infrared spectroscopy

Amyloid found in human cataracts with two-dimensional infrared spectroscopy

In vitro interactions of histones and α-crystallin

Identification of differential gene expression pattern in lens epithelial cells derived from cataractous and non-cataractous lenses of Shumiya cataract rat

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