Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. Current treatments are limited due to our inadequate understanding of the pathogenic events leading to AMD. Early clinical symptoms occur in the retinal pigment epithelium (RPE), suggesting RPE as the potential site of defect in AMD. This research evaluated the RPE proteome and mitochondrial DNA (mtDNA) to test the hypothesis that molecular changes in the RPE contributes to AMD. Human donor eyes categorized into four progressive stages of AMD were utilized in these investigations.
Two proteomic analyses using 2D gel electrophoresis and mass spectrometry were performed to define changes in the RPE proteome. In the first proteomic study, analysis of the mitochondrial proteome revealed significant changes that suggested potential damage to mtDNA with AMD. These results prompted an analysis of mtDNA lesions associated with aging and AMD. These results suggest a potential link between mt dysfunction due to increased mtDNA damage and altered proteins and AMD pathology. In the second study, we tested the hypothesis that mt dysfunction is communicated to the nucleus via retrograde signaling and consequently alters the protein profile to reflect a major shift in metabolism and stress response. Our results suggest not only adjusted metabolism, response to stress and cellular redox regulation but also show major differences in the protein profile with AMD compared to aging.
In summary, our investigations distinguished between normal and pathologic aging by identifying key macromolecules and pathways affected with each process. Furthermore, our data indicate a potential link between mitochondrial dysfunction and AMD pathology, thus providing a point of intervention for the treatment of AMD.
University of Minnesota Ph.D. dissertation. August 2010. Major: Biochemistry, Molecular Bio, and Biophysics. Advisor: Deborah A. Ferrington. 1 computer file (PDF); 1 v. (various pagings), appendices A
Karunadharma, Pabalu Pussellage Ranmini.
Defining AMD disease mechanisms: a comparative analysis of proteins and mitochondrial DNA.
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