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Loreley Denise Robie, Micahla C Brown, Reid A Waldman, Stephanie L Grillo, Nilofer Qureshi, Simon Kaja, Peter Koulen; Altered proteasome subunit expression correlates with vision loss in a preclinical glaucoma model.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6010. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The proteasome, a key regulator of inflammatory processes, is critical for the dysregulation of the activity of individual proteases in a range of diseases and potentially also in glaucoma. As the detailed pathophysiological mechanisms of glaucoma development at the level of the retina and optic nerve remain unknown, recent proteomic studies have implicated the unfolded protein response as a potential contributor, which prompted us to focus on proteasome β subunit expression in the retina. Here we tested the hypothesis that proteasome subunit expression is altered in the glaucomatous retina during beginning vision loss at the onset of disease development.
We utilized 8 week-old (young) non-glaucomatous and 9 months-old (aged) glaucomatous DBA/2J mice, an established preclinical model for human pigmentary glaucoma. Using quantitative polymerase chain reaction (qPCR) and quantitative immunoblotting, we measured the expression levels of proteasome β subunits in the retina. Subsequently, we determined whether proteasome subunit expression was correlated with measures of visual function and disease-related vision loss.
We identified a 3.65-fold increase in expression of Psmb9 mRNA, encoding the LMP2 subunit in glaucomatous retina compared with non-glaucomatous controls. Expression of all other proteasome β subunits did not change in glaucomatous retinas. This increase in message was confirmed at the protein level, where we identified a 195 ± 38% increase in LMP2 protein in the aged glaucomatous retina compared with young non-glaucomatous controls. Increased LMP2 protein levels were associated with decreased visual acuity (P<0.05; r2=0.57) and elevated contrast sensitivity thresholds (P<0.01; r2=0.71).
Our data provide evidence for a differentially altered proteasome subunit composition in the glaucomatous retina. Given the strong association between proteasome subunit expression and functional readouts for glaucoma-mediated vision loss, the proteasome may represent a promising target for future anti-glaucoma drug development efforts, especially given the fact that a single subunit, LMP2, is highly specifically affected while other subunits are not.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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