lanosterol reverse protein aggregation in cataracts

Abstract

Purpose : Cataracts are the most common cause of blindness worldwide, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. We investigated a role of LSS mutations in congenital cataracts in humans and in animal models.

Methods : Exome capture were performed to screen for mutations in the LSS gene in congenital cataracts. LSS mutant knockout mice were generated by CRISPR-Cas technology and their phenotypes characterized.

Results : We identified two distinct homozygous LSS missense mutations (W581R and G588S) in two families with congenital cataracts. Engineered expression of wild-type (WT), but not mutant LSS, prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased pre-formed protein aggregates both in vitro and in cell transfection experiments. We further showed that lanosterol treatment could reduce cataract and increase transparency in dissected rabbit cataract lenses in vitro and cataract in vivo in dogs. The critical role of lanosterol in cataract formation is supported by the observation that LSS missense mutation mouse recapitulates the human cataract disease phenotype.

Conclusions : Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.