# Aggregation of Deamidated Crystallins as a Major Cause of Cataracts

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $398,547

## Abstract

Project Summary:
Our laboratories have focused on the most prevalent chemical modifications that we have identified to be
associated with the insoluble proteins present in the nucleus of the lens- deamidation and oxidation. These
modifications are most relevant to age-related nuclear cataract, by far the most common type of cataract. In
this proposed work, we will examine the interplay between deamidation and oxidation in order to mimic the
age-related processes in the lens. Although the lens environment is normally in a reduced state, oxidation of
sulfhydryls in crystallins has long been associated with age-related cataract as the pool of lens glutathione
diminishes with aging in the center of the lens. The formation of non-native, disulfide crosslinked crystallin
subunits via the oxidation of Cys residues is therefore anticipated to be a key process leading to the
aggregation and insolubilization of lens proteins. In Aim 1, we will determine how specific, age-related
deamidations in γS promote its aggregation by identifying non-native disulfide bond formed in response to
combined deamidation and oxidation. In Aim 2, we will test the hypothesis that non-native disulfide bond
formation leads to higher ordered oligomers of γS. While the focus of Aims 1 and 2 is the oxidation of
deamidated γS, Aim 3 explores whether these age-related modifications in γS lead to non-native crosslinks
between γ- and β-crystallin subunits and thereby disrupt the native quaternary arrangement of the crystallins.
Overall, these findings will elucidate how deamidation, a spontaneous modification, contributes to the
oxidation-driven aggregation cascade that underlies age-related nuclear cataract. Establishing that
deamidation mediates its effects predominantly via augmenting the oxidation of crystallin proteins will provide a
robust model for the development of therapeutic strategies aiming to delay the onset of age-related nuclear
cataract by restoring the antioxidant levels of the lens. The work will also have significant implications for
several other diseases where deamidation and oxidation of long-lived proteins is associated with amyloid fibril
formation.

## Key facts

- **NIH application ID:** 10298668
- **Project number:** 2R01EY027012-02A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** KIRSTEN Jeanne LAMPI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,547
- **Award type:** 2
- **Project period:** 2016-09-30 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298668

## Citation

> US National Institutes of Health, RePORTER application 10298668, Aggregation of Deamidated Crystallins as a Major Cause of Cataracts (2R01EY027012-02A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10298668. Licensed CC0.

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