Systems pathology analysis identifies neurodegenerative nature of age‐related vitreoretinal interface diseases

Abstract

Aging is a phenomenon that is associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision‐threatening vitreoretinal diseases affecting millions of aging people globally, making these conditions an important public health issue. iERM is characterized by fibrous tissue developing on the surface of the macula, which leads to biomechanical and biochemical macular damage. MH is a small breakage in the macula and is associated with many ocular conditions. Although several individual factors and pathways are suggested, a systems pathology level understanding of the molecular mechanisms underlying these disorders is lacking. Therefore, we performed mass spectrometry‐based label‐free quantitative proteomics analysis of the vitreous proteomes from patients with iERM and MH to identify the key proteins, as well as the multiple interconnected biochemical pathways, contributing to the development of these diseases. We identified a total of 1,014 unique proteins, many of which are linked to inflammation and the complement cascade, revealing the inflammation processes in retinal diseases. Additionally, we detected a profound difference in the proteomes of iEMR and MH compared to those of diabetic retinopathy with macular edema and rhegmatogenous retinal detachment. A large number of neuronal proteins were present at higher levels in the iERM and MH vitreous, including neuronal adhesion molecules, nervous system development proteins, and signaling molecules, pointing toward the important role of neurodegenerative component in the pathogenesis of age‐related vitreoretinal diseases. Despite them having marked similarities, several unique vitreous proteins were identified in both iERM and MH, from which candidate targets for new diagnostic and therapeutic approaches can be provided.

Molecular pathogenesis of rhegmatogenous retinal detachment

“…PVR was observed in a total of eight eyes. For comparison, samples of neurodegenerative vitreoretinal interface eyes and proliferative diabetic retinopathy eyes with tractional-retinal detachment (PDR-TRD) were used as a control 15 , 16 . Age distributions of the patients were 59.5 ± 10.1 in RRD group, 64.6 ± 3.4 in MH group, 64.8 ± 3.2 in Pucker group and 45.7 ± 14.2 in PDR-TRD group, showing that the MH and Pucker patients were slightly older and diabetic patients slightly younger than RRD patients (Fig.…”

Proteomic Biomarkers of Retinal Inflammation in Diabetic Retinopathy

“…The use of high throughput proteomics has expanded to include ophthalmic investigations. Numerous studies have been conducted on samples from DR patients including tear, cornea, aqueous humor (AH), lens, vitreous humor (VH), retina, and serum [61] using proteomic approaches such as two-dimensional difference gel electrophoresis (2D-DIGE) coupled with MS [10,20,39,62,63,64,65], SDS-PAGE coupled with MS [16,66], liquid chromatography coupled with tandem MS (LC-MS/MS) [3,4,13,15,17,33,35,56,67,68,69,70,71,72], and bead-based multiplex immunoassays [73,74]. Several well-characterized biomarkers of DR have been identified, including complement component C3, intercellular adhesion molecule 1 (ICAM-1), interleukin-6 (IL-6), serum amyloid A protein (SAA), vascular endothelial growth factor (VEGF), etc.…”

“…Several proteins in the VH have been identified as biomarkers for different stages of DR. Components of the acute phase response (e.g., α-1-antitrypsin, α-1-glycoproteins, interleukins), complement system (e.g., C3), coagulation pathway (e.g., fibrinogen, prothrombin), and other inflammatory pathways (e.g., VEGF, amyloid-β A4 protein, kininogen-1, metalloproteinase inhibitor 1) have been identified by multiple studies in DR [3,4,11,13,15,39,56,62,63,66,70,71,72,118]. Interleukins have been well characterized for their role in promoting inflammation in eyes with DR [66,119,120,121,122,123,124,125].…”

“…Interleukins have been well characterized for their role in promoting inflammation in eyes with DR [66,119,120,121,122,123,124,125]. Additionally, many members of the apolipoprotein family have been identified in the VH [4,39,63,70,126]. A negative regulator of inflammatory processes, pigment epithelium-derived factor (PEDF) has lower levels in VH from DR subjects as compared to subjects without DR, suggesting that there is not only an increase in pro-inflammatory cytokines, but also a decrease in balancing anti-inflammatory proteins [20,62,63].…”

“…Different pathological states may cause changes in the total protein content, as retinal vascular leakage is known to increase the amount of proteins present in the VH and the AH by introducing non-native proteins [2,4,5,22,39,57,65,81,149]. Furthermore, highly abundant proteins like serum albumin, hemoglobin, and crystallins can mask the detection of lower abundance proteins [3,16,20,22,57,63,70,149]. Depletion of the most abundant proteins using column chromatography can ameliorate some of these issues and enrich proteins that are less abundant.…”