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Proteome Remodeling of the Eye Lens at 50 Years Identified with Data-Independent Acquisition

ABSTRACT: The eye lens is responsible for focusing and transmitting light to the retina. The lens does this in the absence of organelles yet maintains transparency for at least five decades before onset of age-related nuclear cataract (ARNC). It is hypothesized that oxidative stress contributes significantly to ARNC formation. It is additionally hypothesized that transparency is maintained by a microcirculation system (MCS) that delivers antioxidants to the lens nucleus and exports small molecule waste. Commonly used data-dependent acquisition (DDA) proteomics methods are hindered by the dynamic range of protein expression in the lens and provide limited context to age-related changes in the lens. In this study we utilized data-independent acquisition (DIA) mass spectrometry proteomics to analyze the urea insoluble, membrane protein fractions of 16 human lenses subdivided into three spatially distinct lens regions to characterize age-related changes, particularly concerning the lens MCS and oxidative stress response. In this pilot cohort, using the DIA approach, we measured 4,788 distinct protein groups, and 46,681 peptides, more than in any previous human lens DDA approach. Our results reveal age-related changes previously known in lens biology and expand on these findings, taking advantage of the rich dataset afforded by DIA mass spectrometry. Principally, we demonstrate that a significant proteome remodeling event occurs at approximately 50 years of age, resulting in metabolic preference for anaerobic glycolysis established with organelle degradation, decreased abundance of protein networks involved in calcium-dependent cell-cell contacts while retaining networks related to oxidative stress response. Further, we demonstrate the first identification of multiple antioxidant transporter proteins not previously shown in the human lens and describe their spatiotemporal and age-related abundance changes. Finally, we demonstrate that Aquaporin-5, among other proteins, is depleted with age. We suggest that the continued accumulation of each of these age-related outcomes in proteome remodeling contribute to decrease in fiber cell permeability and result in ARNC formation.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Kevin Schey

PROVIDER: MSV000089427 | MassIVE | Thu May 05 17:14:00 BST 2022

SECONDARY ACCESSION(S): PXD033722

REPOSITORIES: MassIVE

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Project description:Hui2014 - Age-related changes in articular cartilage This model is described in the article: Oxidative changes and signalling pathways are pivotal in initiating age-related changes in articular cartilage Wang Hui1, David A Young1, Andrew D Rowan1, Xin Xu2, Tim E Cawston1, Carole J Proctor1,3 Annals of the Rheumatic Diseases Abstract: Objective: To use a computational approach to investigate the cellular and extracellular matrix changes that occur with age in the knee joints of mice. Methods: Knee joints from an inbred C57/BL1/6 (ICRFa) mouse colony were harvested at 3–30?months of age. Sections were stained with H&E, Safranin-O, Picro-sirius red and antibodies to matrix metalloproteinase-13 (MMP-13), nitrotyrosine, LC-3B, Bcl-2, and cleaved type II collagen used for immunohistochemistry. Based on this and other data from the literature, a computer simulation model was built using the Systems Biology Markup Language using an iterative approach of data analysis and modelling. Individual parameters were subsequently altered to assess their effect on the model. Results: A progressive loss of cartilage matrix occurred with age. Nitrotyrosine, MMP-13 and anaplastic lymphoma kinase (ALK1) staining in cartilage increased with age with a concomitant decrease in LC-3B and Bcl-2. Stochastic simulations from the computational model showed a good agreement with these data, once transforming growth factor-? signalling via ALK1/ALK5 receptors was included. Oxidative stress and the interleukin 1 pathway were identified as key factors in driving the cartilage breakdown associated with ageing. Conclusions: A progressive loss of cartilage matrix and cellularity occurs with age. This is accompanied with increased levels of oxidative stress, apoptosis and MMP-13 and a decrease in chondrocyte autophagy. These changes explain the marked predisposition of joints to develop osteoarthritis with age. Computational modelling provides useful insights into the underlying mechanisms involved in age-related changes in musculoskeletal tissues. This model is hosted on BioModels Database and identified by: BIOMD0000000560. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Proteome Remodeling of the Eye Lens at 50 Years Identified with Data-Independent Acquisition

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