Animal Models Of Agerelated Cataracts

Overview

Since cataractogenesis is a complex process accompanied by numerous secondary changes, animal models may provide useful information for delineating the causes of senescent and other cataracts. Hereditary cataracts in rodents have been especially useful in this regard (Graw and Loster, 2003). One example is the Philly mouse, which displays an autosomal dominant cataract in which there is a deficiency of ^B2-crystallin polypeptide. The ^B2-crystallin mRNA has a deletion of 12 nucleotides, resulting in a four-amino-acid deletion in the encoded protein. It has been hypothesized that this causes aberrant folding of the protein and that cataract formation occurs as a result of the molecular instability of this crystallin and is therefore a good model to examine the roles of crystallin proteolysis and aggregation in age-related cataract formation. Other models suggest that some metabolic lesions can also cause cataracts. The Nakano mouse, which has autosomal recessive cataracts mapping to chromosome 16, shows reduced synthesis of a- and ^-crystallins. This is probably due to an increase in the Na+/K+ ratio occurring because of inhibition of the sodium-potassium pump. The Fraser mouse, which displays an autosomal dominant cataract, shows preferential loss of y-crystallins and their mRNAs. However, the gene causing this cataract segregates independently of the y-crystallin gene cluster, suggesting that changes in crystallin expression must be secondary in this cataract. It resides on chromosome 10 and has been suggested to be allelic with the mouse lens opacity gene (LOP).

Emory mouse

Unlike the animal cataract models eariler, the Emory mouse is an interesting model for age-related cataracts that has been phenotypically but not molecularly or genetically well-characterized (Kuck, 1990). Two sub-strains of Emory mice in which cataracts develop at five to six months (early cataract strain) and six to eight months (late-cataract strain) are known. Emory mouse cataracts increase in severity with age and are initiated in the lens superficial cortex. They eventually progress into the deep anterior cortex and ultimately result in complete opacification. Emory mouse cataracts exhibit multiple changes that appear to mimic accelerated aging including abnormal lens growth, decreased protein accumulation, conversion of soluble to insoluble protein, decreased reduced glutathione, decreased protein sulf-hydryl levels, decreased superoxide dismutase activities, decreased catalase activity, decreased glutathione perox-idase activity, decreased y-glutamylcysteine synthetase activity, and accelerated conversion of MP26 to MP24. The Emory mouse is also associated with changes in gene expression including decreased synthesis of crystallins and increased expression of ARK tyrosine kinase, which is believed to be a major upstream activator of the stress response in many cell types.

In vivo hyperbaric oxygen treatment Many of the modifications undergone by lens proteins in aging and cataractous lenses are consistent with those seen in photo-oxidative stress, and oxidative stress is known to be a risk factor in age-related cataracts (Giblin et al, 1995). Thus, exposing animals to increased oxygen tension to simulate the more prolonged oxidative stress associated with aging is an attractive and logical model system for understanding human cataract. In these studies, animals are exposed to 100% oxygen at increased pressure several times weekly for two to three months, and lens opacities are monitored by imaging with a slit lamp. Molecular and biochemical changes in the treated animals subsequently are correlated with lens opacity and oxygen treatment. Hyperbaric oxygen treatment in vivo accelerates lens opacity in the nuclear region of the guinea pig lens including loss of water soluble and cyto-skeletal proteins, formation of protein disulfides, and degradation of MIP26. Such modifications are similar to modifications reported to occur in the nuclei of aging and cataractous human lenses, confirming that hyperbaric oxygen treatment is an excellent model to study those processes occurring in human cataracts.

Other

In addition to the preceding models, cell culture, organ culture, and transgenic mice provide powerful tools for the study of lens transparency. Multiple lens epithelial cell lines have been used to identify and functionally analyze those enzymes and other proteins important for resistance to oxidative stress, chaperone function, and other processes associated with cataractogenesis. For instance, the importance of specific enzymes such as methionine sulfoxide reductase and MnSOD for maintaining lens cell viability and resistance to oxidative stress have been identified through the over-expression or silencing of these enzymes in lens cells, which are subsequently treated with H2O2 and/or other oxidants associated with cataracts. Other approaches include similar experiments using lens cells cultured from animal knockouts deleted for specific lens proteins such as aA-crystallin. In addition to cultured lens cells, cultured whole lenses also have been employed to monitor multiple biological events associated with cataracts.

In practice, creation of cataractous transgenic mouse lines is facilitated by the lens being readily examined for transparency, providing a rapid and efficient means to screen for phenotypic effects of transgenic insertions. Most cataracts in transgenic mice are associated with abnormalities of lens development, especially uncontrolled growth, toxic ablation of specific lens cells, or immune destruction of the lens. Lens abnormalities have been caused in transgenic mice using a variety of strategies. Expression of diphtheria toxin or ricin under the control of a lens-specific a-crystallin or y-crystallin promoter, respectively, has caused ablations within the lens.

In addition to transgenic expression of normal or modified proteins, disrupted expression of a protein normally found in the lens has been shown to cause cataracts. Lack of aA-crystallin expression causes cataracts with inclusion bodies in central lens fiber cells (Brady et al., 1997). Other knockouts associated with cataracts include osteonectin, connexins, and glutathione peroxidase. Collectively, these engineered cataract models emphasize the importance of the crystallins, cytoskeleton, and intercellular matrix for lens transparency.

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