The central premise of this proposal is that the lens has evolved several key protective and repair systems that maintain its transparent function and that an age-related decrease in the function of these systems contributes to age-related cataract. A hallmark of human lens aging and cataract formation is oxidation of protein methionines to protein methionine sulfoxide (PMSO). PMSO levels increase in the human lens with age and in human age-related cataract, 60% of total lens protein is found as PMSO. PMSO causes loss of protein function, protein aggregation and cell death. However, to date, the role of PMSO in lens aging and cataract formation has not been established. One key to unlocking the role of PMSO in lens aging and cataract formation is to identify those repair mechanisms that the lens has evolved to defend against PMSO damage and those proteins whose functions are lost upon methionine sulfoxide (MSO) formation. We have discovered that a novel PMSO repair enzyme called methionine sulfoxide reductase A (MsrA) is essential for lens defense against oxidative stress, viability, and defense against cataract formation. Since PMSO accumulates in the human lens with increasing age and since MsrA activity is essential for cataract resistance, it is likely that loss of MsrA repair of one or more lens proteins oxidized to PMSO upon aging and/or oxidative stress contributes to loss of protein function and cataract. A likely target for MsrA repair is ?-crystallin, which exists in the lens as an oligomer of two subunits (? A and ? B) each containing two conserved methionines. In addition to its role as a structural lens crystallin, ? -crystallin is essential for lens function through its ability to act as a molecular chaperone that protects lens proteins against age-related damage. This application will test the hypothesis that oxidation of ? -crystallin to methionine sulfoxide (? -crystallin-MSO) causes loss of chaperone function and that MsrA can repair and restore the chaperone function of ? -crystallin-MSO. Thus, loss of MsrA activity upon aging could result in increased levels of ? -crystallin-MSO, loss of lens chaperone function and ultimately cataract formation. The results of these studies will provide a novel mechanism for cataract development and an innovative model describing the interdependent functions of key lens protective and repair systems. The information gained from this work could have a major impact on the rational design of therapeutics based on increasing the activity of MsrA thereby preventing cataract formation.

Public Health Relevance

The lens has evolved several key protective and repair systems that maintain its transparent function and an age-related decrease in the function of these systems contributes to age-related cataract the leading cause of visual impairment world-wide. The information gained from this work will have a major impact on the rational design of therapeutics that could prevent cataract formation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013022-13
Application #
8213504
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
1999-09-30
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
13
Fiscal Year
2012
Total Cost
$346,800
Indirect Cost
$106,800
Name
Florida Atlantic University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
004147534
City
Boca Raton
State
FL
Country
United States
Zip Code
33431
Chauss, Daniel; Basu, Subhasree; Rajakaruna, Suren et al. (2014) Differentiation state-specific mitochondrial dynamic regulatory networks are revealed by global transcriptional analysis of the developing chicken lens. G3 (Bethesda) 4:1515-27
Costello, M Joseph; Brennan, Lisa A; Basu, Subhasree et al. (2013) Autophagy and mitophagy participate in ocular lens organelle degradation. Exp Eye Res 116:141-50
McGreal, Rebecca S; Brennan, Lisa A; Kantorow, Wanda Lee et al. (2013) Chaperone-independent mitochondrial translocation and protection by ?B-crystallin in RPE cells. Exp Eye Res 110:10-7
McGreal, Rebecca S; Kantorow, Wanda Lee; Chauss, Daniel C et al. (2012) *B-crystallin/sHSP protects cytochrome c and mitochondrial function against oxidative stress in lens and retinal cells. Biochim Biophys Acta 1820:921-30
Kantorow, Marc; Lee, Wanda; Chauss, Daniel (2012) Focus on Molecules: methionine sulfoxide reductase A. Exp Eye Res 100:110-1
Chen, Jianjun; Ma, Zhiwei; Jiao, Xiaodong et al. (2011) Mutations in FYCO1 cause autosomal-recessive congenital cataracts. Am J Hum Genet 88:827-38
Yang, Chunbo; Yang, Ying; Brennan, Lisa et al. (2010) Efficient generation of lens progenitor cells and lentoid bodies from human embryonic stem cells in chemically defined conditions. FASEB J 24:3274-83
Brennan, Lisa A; Lee, Wanda; Kantorow, Marc (2010) TXNL6 is a novel oxidative stress-induced reducing system for methionine sulfoxide reductase a repair of ?-crystallin and cytochrome C in the eye lens. PLoS One 5:e15421
Brennan, Lisa A; Kantorow, Marc (2009) Mitochondrial function and redox control in the aging eye: role of MsrA and other repair systems in cataract and macular degenerations. Exp Eye Res 88:195-203
Brennan, L A; Lee, W; Cowell, T et al. (2009) Deletion of mouse MsrA results in HBO-induced cataract: MsrA repairs mitochondrial cytochrome c. Mol Vis 15:985-99

Showing the most recent 10 out of 33 publications