Systems Pathology Analysis Identifies Neurodegenerative Nature of Age-related Vitreoretinal Interface Diseases

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.