PerspectiveDRUG DISCOVERY

A new dawn for cataracts

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Science  06 Nov 2015:
Vol. 350, Issue 6261, pp. 636-637
DOI: 10.1126/science.aad6303

Cataract, a clouding of the eye lens, is the major cause of blindness in the world, accounting for about 20 million cases (1). Treatment is surgical—the opaque, cataractous lens is replaced with an artificial, plastic one. Many people in the developing world become blind due to cataracts because of a lack of medical resources. A new drug treatment for cataracts based on eye drops would remove this obstacle, as current agents and dietary recommendations are generally ineffective. The findings of Makley et al. (2) reported on page 674 of this issue, and by Zhao et al. (3) may substantially boost the cataract pharmacopoeia.

The lens comprises mainly fiber cells. An epithelium, one cell thick, covers the anterior pole of the lens (4), and a basement membrane, the capsule, defines the lens perimeter (see the figure). Crystallins contribute much to the refractive properties of the lens. CryAA and cryAB are small heat shock protein chaperones (5) that stop lens proteins from forming light-diffracting aggregates. The lens contains some of the oldest proteins in the body (6). Cataracts form when the cryAA and cryAB chaperone function is overwhelmed by the age-dependent accumulation of posttranslationally modified lens proteins and lipids (7), allowing light-scattering protein aggregates and multilamellar bodies (containing many layers of membrane) to form. Presbyopia—farsightedness caused by the loss of lens elasticity—precedes age-related cataract formation (8).

Makley et al. and Zhao et al. identify sterols that improve lens transparency. Both studies link specific sterols to the reversal of cataract in different animal models and ex vivo lens experiments. Makley et al. identified 5-cholesten-3b,25-diol in a small-molecule screen for chemicals that restored the temperature stability of HSP27, a small heat shock protein. It is closely related both structurally and functionally to cryAA and cryAB as protein stabilizing and assembly chaper-ones (5). In two mouse models of inherited human cataract [mutant cryAA (R49C) and cryAB (R120G), where arginine 49 is replaced with cysteine and arginine 120 with glycine, respectively], 5-cholesten-3b,25-diol reduced cataract severity after only a 2-week eye-drop treatment regime. Similarly, Zhao et al. identified mutations in lanosterol synthase as the genetic basis of inherited cataract and found that lanosterol increased lens transparency in a dog model of age-related cataract with a 6-week treatment regime.

Earlier biochemical, genetic, and drug studies indicated an association between cataract and sterols (7). Certain bile acids were shown to increase cryAB and cryAA chaperone activity (9) and prevent cataract in a selenite model of cataract formation in rats (10). Makley et al. and Zhao et al. advance the field by showing that protein aggregation accompanying cataractogenesis is not an endpoint, but can be quickly reversed with specific sterols.

Makley et al. used high-throughput differential scanning fluorimetry to identify 32 compounds active on HSP27, of which 12 were related sterols. As 5a-cholestan-3bol-6-one and 5-cholesten-3b,25-diol are derivatives of a common lipid, cholesterol, they were selected for biochemical analysis. 5-Cholesten-3b,25-diol docked into a groove formed at the cryAB dimer interface to stabilize the native state. Both sterols inhibited the potential of R120G cryAB to unfold and form amyloid-like fibrils. Makley et al. found that lanosterol performed relatively poorly in binding to HSP27 compared to the identified active compounds, indicating that the structure-function relationship for cataract inhibition by sterols is still an open question. Interestingly, Zhao et al. observed that lanosterol dissolved fibers formed by cryAA R116C, R116H, and Y118D mutants (in which arginine 116 is replaced with cysteine or histidine, and tyrosine 118 is replaced with aspartic acid, respectively). Lanosterol also prevented the aggregation of β and γ crystallins in transiently transfected cells. Perhaps lanosterol activates endogenous small heat shock proteins, as evidence from Makley et al. suggests that lanosterol does not bind directly to β or γ crystallins.

Getting clearer.

Cataractogenesis involves the aggregation of crystallin (and other) proteins as well as multilamellar bodies in the lens. CryAA and cryAB prevent such aggregates, but less so during aging. Lanosterol and two cholesterol derivatives (not shown) reversed cataract formation in animal models and ex vivo lenses. CryAA and cryAB may act as sensors that solubilize aggregates in response to such sterols, which will also modulate membrane lipid domains in the lens.

GRAPHIC: P. HUEY/SCIENCE

Lanosterol is a precursor of cholesterol, pointing to cholesterol metabolism as a key factor in cataract formation. This complements clinical observations in certain disorders. Patients with Smith-Lemli-Opitz syndrome have an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol reductase; 20% of affected individuals have cataracts. Mevalonic aciduria is caused by a deficiency of mevalonate kinase, which results in a defect in the biosynthesis of cholesterol and isoprenoids; cataract is an ophthalmic feature of this disorder. Cerebrotendinous xanthomatosis patients also present with cataract. This is a fat storage disorder caused by the inability to metabolize certain lipids, including cholesterol. Also, the debate over the increased cataract risk with statin use continues (11), but now there is reason for caution. Statins are cholesterol-lowering drugs that inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, an enzyme in the cholesterol biosynthesis pathway.

Both cryAB and cryAA bind to cell membranes, possessing high- and low-affinity binding sites (7). As lens cells age, more of the soluble crystallin proteins associate with membranes, and cryAA and cryAB become even more membrane-embedded (7). Both 5-cholesten-3b,25-diol and lanosterol increase lens protein solubility, but the mechanism was unexplored by Makley et al. or Zhao et al. The promoter region of the cryAA and cryAB genes contains sterol responsive element (12, 13), adding a potential transcriptional mechanism to the posttranslational mechanism for integrating chaperone function and cholesterol biosynthesis and metabolism.

There is still much to learn about sterols, small heat shock proteins, and the physiological importance of their interaction and their diverse roles in lens function, presbyopia, and cataractogenesis. Perhaps these chaperones are a new class of sterol sensors, tuned to cholesterol metabolism and cholesterol modifications in the eye lens. Moreover, cryAB functions in many other cellular processes, including the cell division cycle, programmed cell death, cytoskeletal dynamics, and redox balance (14). The potential to apply the discovery of Makley et al. and Zhao et al. to cataract, presbyopia, and protein misfolding diseases that involve these small heat shock proteins and their clients now beckons.

References

  1. www.who.int/blindness/causes/priority/en/index1.html
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