Protein Aggregation and Cataract: Role of Age-Related Modifications and Mutations in α-Crystallins

Cataract is a major cause of blindness. Due to the lack of protein turnover, lens proteins accumulate age-related and environmental modifications that alter their native conformation, leading to the formation of aggregation-prone intermediates, as well as insoluble and light-scattering aggregates, thus compromising lens transparency. The lens protein, alpha-crystallin, is a molecular chaperone that prevents protein aggregation, thereby maintaining lens transparency. However, mutations or post-translational modifications, such as oxidation, deamidation, truncation and crosslinking, can render alpha-crystallins ineffective and lead to the disease exacerbation. Here, we describe such mutations and alterations, as well as their consequences. Age-related modifications in alpha-crystallins affect their structure, oligomerization, and chaperone function. Mutations in alpha-crystallins can lead to the aggregation/intracellular inclusions attributable to the perturbation of structure and oligomeric assembly and resulting in the rearrangement of aggregation-prone regions. Such rearrangements can lead to the exposure of hitherto buried aggregation-prone regions, thereby populating aggregation-prone state(s) and facilitating amorphous/amyloid aggregation and/or inappropriate interactions with cellular components. Investigations of the mutation-induced changes in the structure, oligomer assembly, aggregation mechanisms, and interactomes of alpha-crystallins will be useful in fighting protein aggregation-related diseases.

Automated summary

Cataract is a major cause of blindness, potentially caused by mutations or age-related modifications in lens proteins that lead to protein aggregation and compromise lens transparency. The lens protein alpha-crystallin acts as a molecular chaperone to prevent protein aggregation, but mutations or modifications can render it ineffective and worsen the disease.