Protein misfolding and aggregation in cataract disease and prospects for prevention

Abstract

The transparency of the eye lens depends on maintaining the native tertiary structures and solubility of the lens crystallin proteins over a lifetime. Cataract, the leading cause of blindness worldwide, is caused by protein aggregation within the protected lens environment. With age, covalent protein damage accumulates through pathways thought to include UV radiation, oxidation, deamidation, and truncations. Experiments suggest that the resulting protein destabilization leads to partially unfolded, aggregation-prone intermediates and the formation of insoluble, light-scattering protein aggregates. These aggregates either include or overwhelm the protein chaperone content of the lens. Here we review the causes of cataracts and non-surgical methods being investigated to inhibit or delay cataract development, including natural product-based therapies, modulators of oxidation, and protein aggregation inhibitors.

Impediment of selenite-induced cataract in rats by combinatorial drug laden liposomal preparation

“…More than half the cases of blindness across the world are a result of cataract which is a serious condition of opacification of lenses caused by protein aggregation [1,2]. Transparency and refraction of lens is a cumulative effect of the crystalline protein present in high concentrations [3].…”

Biophysical chemistry of the ageing eye lens

“…The eye lenses of all mammals are composed of fibre cells arranged in concentric layers around a central nucleus (Moreau and King 2012) (Fig. 2).…”

“…While this lack of organelle-like sub-structure means the lens fibre cells have exceptional optical properties, it also means that once they have matured they have very little capacity to recycle or repair damaged proteins and no capacity to express new protein (Bloemendal et al 2004;Wang et al 2004). (Moreau and King 2012) The long life of the fibre cells is one of the defining features of the eye lens (Sharma and Santhoshkumar 2009). Due to the lack of protein turnover in the lens fibre cells, crystallin proteins must last the lifetime of each individual.…”

“…The protein composition of a young lens can be very different to that of an aged lens. The aged eye is prone to diseases that result in loss of vision, the most common of which is cataract in the nucleus of the lens (Hains and Truscott 2007;Moreau and King 2012;Truscott 2005).…”

“…The crystallin proteins of the lens are particularly long-lived and any age-related damage they suffer typically accumulates. Cataract occurs when these proteins aggregate into large bodies which cause light scattering and loss of visual acuity (Moreau and King 2012). While the lens has systems to prevent protein aggregation (Ecroyd and Carver 2009;Horwitz 2003), the build-up of damaging modifications over time will eventually overwhelm them and aggregate formation results.…”