Proteomic analysis of aged and OPTN E50K retina in the development of normal tension glaucoma.

Abstract

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.

• Authors: Xinna Liu, Qi Wang, Zhengbo Shao, Shiqi Zhang, Mingying Hou, Menglu Jiang, Mengxian Du, Jing Li, Huiping Yuan
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 30 Issue 11 Pg. 1030-1044 (05 31 2021) ISSN: 1460-2083 [Electronic] England
• PMID: 33856034 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021 . Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Cell Cycle Proteins
• Membrane Transport Proteins
• OPTN protein, human
• Optn protein, mouse
• Transcription Factor TFIIIA

Topics

• Animals
• Autophagy (genetics)
• CRISPR-Cas Systems (genetics)
• Cell Cycle Proteins (genetics)
• Disease Models, Animal
• Humans
• Low Tension Glaucoma (genetics, metabolism, pathology)
• Membrane Transport Proteins (genetics)
• Mice
• Mutation (genetics)
• Phenotype
• Proteomics
• Retina (metabolism, pathology)
• Retinal Ganglion Cells (metabolism, pathology)
• Transcription Factor TFIIIA