Retinal protein changes with age-related macular degeneration

Age-related macular degeneration (AMD) is a progressive eye condition that results in central vision loss. It is the leading cause of legal blindness in adults over the age of 60. Although clinical detection and diagnosis of the disease is fairly straightforward, the molecular causes of the disease are unknown. Consequently no treatments exist that prevent or reverse the disease process.; AMD is a complex, multigenic disease and therefore requires a broad approach, such as proteomics, to facilitate understanding the disease mechanism. Proteomic technology was employed to detect proteins that are altered with AMD. Two-dimensional gels and mass spectrometry were used to identify retinal proteins that were altered in content or oxidatively modified from human donor eyes classified into four distinct stages of AMD. The majority of proteins identified in this study were altered in both the macular and peripheral regions showing the damage is not limited to the macula but rather affects the whole retina. Proteins involved in microtubule regulation and stress response were altered in content at early stages of the disease. Proteins involved in energy production and stress response were consistently modified by 4-hydroxy-2-nonenal, although no stage-specific accumulation was observed.; Proteomic analysis revealed that several proteins involved in the proteasome pathway were also altered in expression. We found that the proteasome, the major protease in the cell, is altered in both activity and subunit composition with the progression of AMD. Proteasome transformation from constitutive to the immunoproteasome may reflect retinal response to local inflammation or oxidative stress with AMD.; In summary, categorization of human donor eyes into distinct stages of the disease allowed for the detection of many retinal protein changes that were occurring with AMD. This information expands our understanding of the molecular details of AMD and will help direct the focus towards "proteins of pathology". Understanding disease mechanisms is requisite to development of new treatments that benefit patients at even the earliest stages of the disease.