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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\u2019s 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddab099","type":"journal-article","created":{"date-parts":[[2021,4,3]],"date-time":"2021-04-03T11:08:39Z","timestamp":1617448119000},"page":"1030-1044","source":"Crossref","is-referenced-by-count":25,"title":["Proteomic analysis of aged and OPTN E50K retina in the development of normal tension glaucoma"],"prefix":"10.1093","volume":"30","author":[{"given":"Xinna","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China"},{"name":"The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry Education, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China"},{"name":"The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry Education, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengbo","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China"},{"name":"Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China"},{"name":"The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry Education, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingying","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China"},{"name":"The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry Education, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menglu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China"},{"name":"Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxian","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China"},{"name":"Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China"},{"name":"Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiping","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,4,15]]},"reference":[{"key":"2021070819101797700_ref1","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1001\/jama.2014.3192","article-title":"The pathophysiology and treatment of glaucoma, a review","volume":"311","author":"Weinreb","year":"2014","journal-title":"JAMA"},{"key":"2021070819101797700_ref2","first-page":"1641","article-title":"The prevalence of primary open-angle glaucoma in Japanese, the Tajimi study","volume":"111","author":"Iwase","year":"2004","journal-title":"Ophthalmology"},{"key":"2021070819101797700_ref3","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1016\/j.ophtha.2011.02.050","article-title":"Prevalence of glaucoma in a rural northern China adult population, a population-based survey in kailu county, Inner 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Retin. Eye Res."},{"key":"2021070819101797700_ref5","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-017-17241-0","article-title":"661W is a retinal ganglion precursor-like cell line in which glaucoma-associated optineurin mutants induce cell death selectively","volume":"7","author":"Sayyad","year":"2017","journal-title":"Sci. Rep."},{"key":"2021070819101797700_ref6","doi-asserted-by":"crossref","first-page":"2690","DOI":"10.1016\/j.bbrc.2018.08.025","article-title":"Optineurin E50K triggers BDNF deficiency-mediated mitochondrial dysfunction in retinal photoreceptor cell line","volume":"503","author":"Shim","year":"2018","journal-title":"Biochem. Biophs. Res. 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