Lanosterol and cataracts: ChEBI entity of the month

The lens of the eye is made up of many millions of thin fibrous cells that contain water-soluble structural proteins known as crystallins. These proteins are among the densest of human tissues and their main function is to increase the refractive index of the lens while not obstructing light. Despite their name, crystallins have been selected by evolution for their tendency not to form crystals – the presence of small crystals or aggregates within the lens would scatter light, so making the lens opaque.

There are three types of crystallin: α (the most common), β, and γ. α-Crystallins are composed of two similar types of protein chain which associate into large spherical complexes, containing around 40 chains, that repel each other and so spread themselves throughout the lens cells. β-Crystallins also form oligomeric complexes, usually containing either two or six copies of the chain. There are a number of similar β-crystallins, which can "mix and match" to give a large number of different types of oligomers. γ-Crystallins, in contrast, are monomeric, and appear to act as a weak glue that binds the α-crystallins gently together [1].

As we age, crystallins may unfold or be oxidised or otherwise damaged. As the damage builds up, so opaque clumps are formed which scatter light, leading to a cloudiness in the lens, eventually resulting in a cataract. Cataracts are the cause of a third of all visual impairment in the world and half of all blindness; they are the most common cause of vision loss in people over the age of 40 [2]. Treatment is by surgery: a small incision is made in the eye to allow the affected lens to be removed and replaced by a plastic lens, called an intraocular implant or intraocular lens. It is one of the most common surgical procedures – more than 300,000 such operations are performed each year in the UK alone [3].

Lanosterol: recent research

Recent work by a team of Chinese researchers suggests that an alternative treatment strategy may be possible [4]. The team studied the DNA of two families with a genetic predisposition to cataracts and found two mutations in the LSS gene, which codes for lanosterol synthase, an enzyme that catalyses the conversion of (S)-2,3-epoxysqualene to lanosterol (CHEBI:16521). This conversion is a key rate-limiting step in the biosynthesis of cholesterol, steroid hormones, and vitamin D. When cloudy lenses taken from rabbits were treated in vitro with lanosterol, the team found that the clumps of damaged proteins were broken up and the lenses became significantly clearer; use of cholesterol instead of lanosterol was ineffective. In a subsequent in vivo study, they found that administering eye drops containing lanosterol for six weeks to dogs suffering from naturally occurring cataracts resulted in a reduction in the severity of the cataracts and in improved lens clarity.

Cataract surgery is an effective, generally safe, relatively straightforward and cheap procedure. It is normally performed using a local anaesthetic and takes around 30 to 45 minutes; an allaboutvision.com report found that in 2012, the average cost of straightforward cataract surgery in the US was $3,429 per eye. Nevertheless, it requires the services of a skilled practitioner, while ageing populations around the world are predicted to require a doubling of cataract surgery within 20 years. A drug that would fix a cataract without the need for surgery would therefore represent a major advance.

Pictured: The chemical structure of lanosterol superimposed on a detail from a Creative Commons licensed photograph of a human eye, taken from Wikimedia Commons.

References

1. Goodsell DS (2010) Crystallins. RCSB PDB Molecule of the Month, July
2. World Health Organisation (2012) Global Data on Visual Impairments 2010
3. Cataract surgery. NHS Choices: Health A to Z.
4. Zhao L, Chen, X-J, Zhu J, et al. (2015) Lanosterol reverses protein aggregation in cataracts. Nature 523:607–611