Gene expression sequence alteration and impaired proteolysis: are they contributory in glaucoma?


Beau Freedman

Hayden Sandler

Shawn M. Iverson

Dianne Barrett

Bryan Alfonso

Richard Lee

Sanjoy K. Bhattacharya

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Purpose: To determine whether expression sequence of extracellular matrix (ECM) proteins/cochlin is altered
in the trabecular meshwork (TM) in glaucoma and specifically whether cochlin degradation is impaired in glaucoma.
Methods: Analysis of expression of cochlin and other genes due to pressure and stretching using the available literature and Gene Expression Omnibus (GEO) database analysis. Determination of transcription factor binding sites on DNA regulatory elements by means of bioinformatics approaches utilizing Genomatix software. For analysis of the degradome, qualitative, labeled quantitative mass spectrometry, cochlin immunoprecipitation, and yeast two-hybrid analysis was performed.
Results: Aberrant accumulation of proteins hinders aqueous outflow in glaucoma. The accumulation may result due to overexpression, lack of degradation, or a combination of both. The overexpression may occur simultaneous with aberration in the sequence of gene expression. Altered gene sequence has potentially negative consequences for organisms. In bacteria, the restriction endonucleases are designed to protect against foreign DNA. The expression of restriction endonuclease is sequenced after modification methyltransferase. The alteration of methyltransferase sequence becomes detrimental for bacteria. We speculate that expression sequence alteration may be associated with the pathogenesis of glaucoma. Using cochlin expression as an example, we provide a conceptual framework as to how to investigate alterations of protein expression sequence in normal vs glaucoma. This is challenging due to the constitutive low-level expression of several proteins, rendering it difficult to determine the actual sequence of expression. The pathologic state may be associated with the level of expression changes (overexpression) rather than from no expression to expression (none to all). Another issue is degradation or lack of degradation that also causes accumulation of proteins.
Conclusion: Overexpression and reduced degradation may be the subtle causes for accumulation of ECM proteins in the TM. In this chapter, we discuss both aspects and speculate that they may be contributory to the pathogenesis of glaucoma. The increased accumulation of proteins in the basement membrane and interstitial spaces contribute to impeded outflow,  resulting in fluid buildup and altered intraocular pressure homeostasis.

Glaucoma Research 2020-2022, pp. 45-56 #5
Edited by: Paul A. Knepper and John R. Samples
© Kugler Publications, Amsterdam, The Netherlands


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