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

Prashanth Budnar1, Ramakrishna Tangirala1, Raman Bakthisaran1, and Ch. Mohan Rao1,a,b**

1Centre for Cellular and Molecular Biology (CCMB), Council of Scientific and Industrial Research (CSIR), Uppal Road, Hyderabad 500007, India

* The article is published as a part of the Special Issue “Protein Misfolding and Aggregation in Cataract Disorders” (Vol. 87, No. 2).

** To whom correspondence should be addressed.

Received October 5, 2021; Revised February 2, 2022; Accepted February 2, 2022
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, α-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 α-crystallins ineffective and lead to the disease exacerbation. Here, we describe such mutations and alterations, as well as their consequences. Age-related modifications in α-crystallins affect their structure, oligomerization, and chaperone function. Mutations in α-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 α-crystallins will be useful in fighting protein aggregation-related diseases.
KEY WORDS: cataract, aggregation, α-crystallin

DOI: 10.1134/S000629792203004X