Lanosterol reversal of protein aggregation in cataract

Summary The human lens is comprised largely of crystalline proteins assembled into a highly ordered, interactive macro‐structure essential for lens transparency. Any disruption of protein interactions will alter this delicate structure, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins prevent aggregation and 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. Here we identify two distinct homozygous LSS missense mutations in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell‐transfection experiments. 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.