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Abstract #94895 Published in IGR 22-2
Proteomic analysis of aged and OPTN E50K retina in the development of normal tension glaucoma
Liu X; Wang Q; Shao Z; Zhang S; Hou M; Hou M; Jiang M; Du M; Li J; Yuan HHuman Molecular Genetics 2021; 30: 1030-1044
Progressive degeneration of retinal ganglion cells (RGCs) is a major characteristic of glaucoma, whose underlying mechanisms are still largely unknown. An E50K mutation in the Optineurin (OPTN) gene is a leading cause of normal tension glaucoma (NTG), directly affecting RGCs without high intraocular pressure and causing severe glaucomatous symptoms in clinical settings. A systematic analysis of the NTG mouse model is crucial for better understanding of the underlying pathological mechanisms for glaucoma. To elucidate proteomic and biochemical pathway alterations during NTG development, we established an OPTN E50K mutant mouse model through CRISPR/Cas9. Retinal proteins from resulting mice exhibiting glaucomatous phenotypes were subject to tandem mass tag-labeled quantitative proteomics and then analyzed through bioinformatics methods to characterize the molecular and functional signatures of NTG. We identified 6364 quantitative proteins in our proteomic analysis. Bioinformatics analysis revealed that OPTN E50K mice experienced protein synthesis dysregulation, age-dependent energy defects and autophagy-lysosome pathway dysfunction. Certain biological features, including amyloid deposition, RNA splicing, microglia activation and reduction of crystallin production, were similar to Alzheimer's disease. Our study is the first to describe proteomic and biochemical pathway alterations in NTG pathogenesis during disease advancement. Several proteomic signatures overlapped with retinal changes found in the ad mice model, suggesting the presence of common mechanisms between age-related degenerative disorders, as well as prospective new targets for diagnostic and therapeutic strategies.
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Classification:
9.2.4 Normal pressure glaucoma (Part of: 9 Clinical forms of glaucomas > 9.2 Primary open angle glaucomas)
3.12 Proteomics (Part of: 3 Laboratory methods)
3.4.2 Gene studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)