A Perspective on Biophysical Studies of Crystallin Aggregation and Implications for Cataract Formation

Lens crystallins are subject to various types of damage during their lifetime which triggers protein misfolding and aggregation, ultimately causing cataracts. There are several models for crystallin aggregation, but a comprehensive picture of the mechanism of cataract is still underway. The complex biomolecular interactions underlying crystallin aggregation have motivated major efforts to resolve the structural details and mechanism of aggregation using multiple biophysical techniques at different resolutions. Together, experimental and computational approaches identify and characterize both amyloidogenic and amorphous aggregates leading to an improved understanding of crystallin aggregation. A rigorous characterization of the aggregation-prone intermediates is crucial in cataract-mediated drug discovery. This Perspective summarizes recent biophysical studies on lens crystallin aggregation. We evaluate the outstanding challenges, future outlook, and rewards in this fertile field of research. With lessons learned from protein folding and multiple pathways of aggregation, we highlight the differences in the overall mechanisms of age-related and congenital cataracts. We expect that a correlation between the existing and developing biophysical techniques would provide a platform to study amyloid architecture in the eye lens and reduce the existing gaps in our understanding of crystallin biophysics.